2-aminothiazoline derivatives and process for preparing the same

ABSTRACT

The present invention relates to a class of 2-aminothiazoline derivatives of formula I:                    
     in which either R 1  is a hydrogen atom or an alkyl radical and R 2  is an alkyl, -alk-NH 2 , —CH 2 —R 3 , —CH 2 —S—R 4  or phenyl radical substituted with a nitro or —NH—C(═NH)CH 3  radical, or R 1  is an alkyl radical and R 2  is a hydrogen atom, R 3  is a (3-6C) cycloalkyl, pyridyl, pyridyl N-oxide, thienyl, thiazolyl, imidazolyl, pyrazinyl, triazolyl or phenyl radical or a phenyl radical substituted with a nitro, hydroxy or carboxyl radical, R 4  represents a pyridyl or pyridyl N-oxide radical, alk represents an alkylene radical, or pharmaceutically acceptable salts thereof, which are useful as inhibitors of inducible NO-synthase.

This application is a division of U.S. application Ser. No. 09/878,814,filed Jun. 8, 2001, now U.S. Pat. No. 6,451,821, which claims thebenefit of U.S. Provisional Application No. 60/232,038, filed Sep. 12,2000, which claims the benefit of priority of French Patent ApplicationNo. 00/07,397, filed Jun. 09, 2000.

The present invention relates to the use of 2-aminothiazolinederivatives of formula (I):

or pharmaceutically acceptable salts thereof, as inhibitors of inducibleNO-synthase.

The subject of the invention is the use of 2-aminothiazoline derivativesof formula (I) and pharmaceutically acceptable salts thereof, for thepreparation of pharmaceutical compositions intended for preventing andtreating diseases in which an abnormal production of nitric oxide (NO)by induction of inducible NO-synthase (NOS-2 or iNOS) is involved, thepharmaceutical compositions containing the novel 2-aminothiazolinederivatives and the pharmaceutically acceptable salts thereof, and thenovel 2-aminothiazoline derivatives and the pharmaceutically acceptablesalts thereof.

Nitric oxide (NO) is a diffusable radical involved in many physiologicaland pathological processes. It is synthesized by oxidation ofL-arginine, this reaction being catalyzed by a family of enzymes knownas nitric oxide synthases or NO-synthases (NOSs), which is referenced inthe international enzyme nomenclature system under the number E.C.1.14.13.39.

Three NOS isoforms, two of which are constitutive and one inducible, areknown:

a neuronal NOS (NOS-1 or NNOS) was originally isolated and cloned fromnerve tissue in which it is a constitutive enzyme. NOS-1 produces NO inresponse to various physiological stimuli such as the activation ofmembrane receptors according to a mechanism dependent on calcium and oncalmodulin;

an inducible NOS (NOS-2 or iNOS) can be induced in response toimmunological stimuli such as, for example, cytokines or bacterialantigens in various cells such as, for example, macrophages, endothelialcells, hepatocytes, glial cells, as well as many other types of cell.The activity of this isoform is not regulated by calcium. Consequently,once induced, it produces large amounts of NO over prolonged periods.

an endothelial NOS (NOS-3 or eNOS) is constitutive andcalcium/calmodulin-dependent. It was originally identified in vascularendothelial cells, in which it generates NO in response to physiologicalstimuli such as the activation of membrane receptors.

The NO produced by the neuronal and endothelial constitutive isoforms(NOS-1 and NOS-3) is generally involved in intercellular signallingfunctions. For example, the endothelial cells which line the inner wallof the blood vessels induce the relaxation of the underlying smoothmuscle cells via the production of NO. It thus contributes towardsregulating the arterial pressure.

The NO produced in large amount by the inducible isoform NOS-2 is, interalia, involved in pathological phenomena associated with acute andchronic inflammatory processes in a large variety of tissues and organs.

An excessive production of NO by induction of NOS-2 thus plays a part indegenerative pathologies of the nervous system such as, for example,multiple sclerosis, cerebral, focal or global ischemia, cerebral orspinal trauma, Parkinson's disease, Huntington's disease, Alzheimer'sdisease, amiotrophic lateral sclerosis, migraine, depression,schizophrenia, anxiety and epilepsy. Similarly, aside from the centralnervous system, the induction of NOS-2 is involved in numerouspathologies with inflammatory components, such as, for example,diabetes, atherosclerosis, myocarditis, arthritis, arthrosis, asthma,irritable bowel syndrome, Crohn's disease, peritonitis,gastro-esophageal reflux, uveitis, Guillain-Barré syndrome,glomerulonephritis, lupus erythematosus and psoriasis. NOS-2 has alsobeen implicated in the growth of certain forms of tumors such as, forexample, epitheliomas, adenocarcinoma or sarcoma, and in infections withGram-positive or Gram-negative intracellular or extracellular bacteria.

In all the situations in which an overproduction of NO is deleterious,it thus appears to be desirable to reduce the production of NO byadministering substances capable of inhibiting NOS-2. However, given theimportant physiological roles played by the constitutive isoform NOS-3,in particular in regulating arterial pressure, it is of fundamentalimportance that the inhibition of the isoform NOS-2 should have theleast possible effect on the isoform NOS-3. The reason for this is thatit is known that the administration of unselective inhibitors of the NOSisoforms leads to vasoconstriction and an increase in arterial pressure(Moncada, S., Palmer, R. M. J. and Higgs, E. A., Biosynthesis of nitricoxide from L-arginine: a pathway for the regulation of cell function andcommunication, Biochem. Pharmacol., 1989, 38: 1709-1715). These effectson the cardiovascular system are deleterious since they reduce thesupply of nutrients to the tissues. Consequently, the present inventionrelates to compounds whose inhibitory activity with respect to NOS-2 issignificantly higher than their inhibitory activity with respect toNOS-3.

Thiazoline-based NOS inhibitors are described in particular in patentapplications WO 94/12165, WO 95/11231 and WO 96/14842.

The present invention relates to the use of 2-aminothiazolinederivatives of formula (I) in which: either R₁ is a hydrogen atom or analkyl radical and R₂ is an alkyl, -alk-NH₂, —CH₂—R₃, —CH₂—S—R₄ or phenylradical substituted with a nitro or —NH—C(═NH)CH₃ radical,

or R₁ is an alkyl radical and R₂ is a hydrogen atom, R₃ is a (3-6C)cycloalkyl, pyridyl, pyridyl N-oxide, thienyl, thiazolyl, imidazolyl,pyrazinyl, triazolyl or phenyl radical or a phenyl radical substitutedwith a nitro or carboxyl radical,

R₄ represents a pyridyl or pyridyl N-oxide radical, alk represents analkylene radical for the preparation of medicinal products that areuseful for preventing or treating diseases in which an abnormalproduction of nitric oxide (NO) by induction of inducible NO-synthase(NOS-2 or iNOS) is involved.

In the above definitions and in those which follow, the alkyl andalkylene radicals contain 1 to 6 carbon atoms in a straight or branchedchain.

The compounds of formula (I) contain one or more asymmetric carbons andcan thus be in racemic form or in the form of enantiomers anddiastereoisomers; these also form part of the invention, along withmixtures thereof.

Moreover, the compounds of formula (I) can be in the tautomeric form(Ia):

These tautomers also form part of the invention.

Among the compounds of formula (I) that are useful according to theinvention, mention may be made of the following compounds:

4-(3-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

4-(3-nitrobenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine

4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine

4-(3-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

4-(2-thienylmethyl)-4,5-dihyro-1,3-thiazol-2-ylamine

[3-(2-amino-4,5-dihydrothiazol-4-yl)phenyl](1-iminoethyl)amine

4-benzyl-4,5-dihydro-1,3-thiazol-2-ylamine

4-(3-carboxybenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine

4-(4-aminobutyl)-4,5-dihydro-1,3-thiazol-2-ylamine

4-butyl-4,5-dihydro-1,3-thiazol-2-ylamine

5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine

4-cyclohexylmethyl-4,5-dihydro-1,3-thiazol-2-ylamine

4-(3-nitrophenyl)-4,5-dihydro-1,3-thiazol-2-ylamine

4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

5-methyl-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

5-ethyl-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

4-(4-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

4-(1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

4-(2-pyrazinylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

4-(5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

4-(4-hydroxybenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine

4-(4-pyridylsulphanylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

4-(3-aminopropyl)-4,5-dihydro-1,3-thiazol-2-ylamine

4-(1-triazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine N-oxide

the racemic mixtures, enantiomers, diastereoisomers and tautomersthereof, as well as the pharmaceutically acceptable salts thereof, andmost particularly the following compounds:

(+)-(4R)-4-(3-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

(+)-(4R)-4-(3-nitrobenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine

(+)-(4R,5S)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine

(+)-(4R,5R)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine

(−)-(4R)-4-(3-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

(4R)-4-(2-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

[3-(2-amino-4,5-dihydrothiazol-4-yl)phenyl](1-iminoethyl)amine

(+)-(4R)-4-benzyl-4,5-dihydro-1,3-thiazol-2-ylamine

(+)-(4R)-4-(3-carboxybenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine

(+)-(4R)-4-(4-aminobutyl)-4,5-dihydro-1,3-thiazol-2-ylamine

(−)-(4S)-4-(3-nitrobenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine

(−)-(4S,5S)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine

(−)-(4S)-4-(4-aminobutyl)-4,5-dihydro-1,3-thiazol-2-ylamine

(4S,5R)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine

(−)-(4R)-4-butyl-4,5-dihydro-1,3-thiazol-2-ylamine

(+)-(5S)-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine

(−)-(4S)-4-cyclohexylmethyl-4,5-dihydro-1,3-thiazol-2-ylamine

(+)-(4R)-4-cyclohexylmethyl-4,5-dihydro-1,3-thiazol-2-ylamine

4-(3-nitrophenyl)-4,5-dihydro-1,3-thiazol-2-ylamine

(+)-(4R)-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

(+)-(4R,5R)-5-methyl-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

(+)-(4R,5R)-5-ethyl-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

(+)-4-(5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

(−)-4-(5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

(+)-(4R)-4-(2-pyrazinylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

(4R)-4-(1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

(4S)-4-(1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

(+)-(4R)-4-(4-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

(+)-(4R)-4-(3-aminopropyl)-4,5-dihydro-1,3-thiazol-2-ylamine

(+)-(4R)-4-(4-hydroxybenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine

(+)-(4-(4-pyridylsulphanylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

(4R)-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine N-oxide

(+)-4-(1-triazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

the tautomers thereof, as well as the pharmaceutically acceptable saltsthereof.

The compounds which are particularly preferred are the useful compoundsof formula (I) according to the invention for which R₁ is a hydrogenatom or an alkyl radical and R₂ is an -alk-NH₂ radical or a phenylradical substituted with an —NH—C(═NH)CH₃, —CH₂—R₃ or —CH₂—S—R₄ radicaland R₃ is a pyridyl, thienyl, thiazolyl, imidazolyl, pyrazinyl,triazolyl or phenyl radical or phenyl radical substituted with a nitroor carboxyl radical, R₄ is a pyridyl radical.

In particular, when R₂ is a —CH₂—R₃ or —CH₂—S—R₄ chain, R₃ is a 3- or4-pyridyl, 2- or 3-thienyl, 4- or 5-thiazolyl, 1-imidazolyl,1-triazolyl, 2-pyrazinyl or phenyl radical or a phenyl radicalsubstituted in position −3 with a nitro or carboxyl radical and R₄ is a4-pyridyl radical.

Among the compounds which are useful according to the invention andparticularly preferred, mention may be made of the following compounds:

4-(3-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

4-(3-nitrobenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine

4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine

4-(3-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

4-(2-thienylmethyl)-4,5-dihyro-1,3-thiazol-2-ylamine

[3-(2-amino-4,5-dihydrothiazol-4-yl)phenyl](1-imino-ethyl)amine

4-benzyl-4,5-dihydro-1,3-thiazol-2-ylamine

4-(3-carboxybenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine

4-(4-aminobutyl)-4,5-dihydro-1,3-thiazol-2-ylamine

4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

5-methyl-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

5-ethyl-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

4-(4-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

4-(1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

4-(2-pyrazinylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

4-(5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

4-(4-pyridylsulphanylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

4-(1-triazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

the racemic mixtures, enantiomers, diastereoisomers and tautomersthereof, as well as the pharmaceutically acceptable salts thereof, andin particular the following compounds:

(+)-(4R)-4-(3-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

(+)-(4R)-4-(3-nitrobenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine

(+)-(4R,5S)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine

(+)-(4R,5R)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine

(−)-(4R)-4-(3-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

(4R)-4-(2-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

[3-(2-amino-4,5-dihydrothiazol-4-yl)phenyl](1-iminoethyl)amine

(+)-(4R)-4-benzyl-4,5-dihydro-1,3-thiazol-2-ylamine

(+)-(4R)-4-(3-carboxybenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine

(+)-(4R)-4-(4-aminobutyl)-4,5-dihydro-1,3-thiazol-2-ylamine

(−)-(4S)-4-(3-nitrobenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine

(−)-(4S,5S)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine

(−)-(4S)-4-(4-aminobutyl)-4,5-dihydro-1,3-thiazol-2-ylamine

(4S,5R)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine

(+)-(4R)-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

(+)-(4R,5R)-5-methyl-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

(+)-(4R,5R)-5-ethyl-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

(+)-4-(5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

(−)-4-(5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

(+)-(4R)-4-(2-pyrazinylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

(4R)-4-(1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

(4S)-4-(1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

(+)-(4R)-4-(4-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

(+)-4-(4-pyridylsulphanylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

(+)-4-(1-triazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

the tautomers thereof, as well as the pharmaceutically acceptable saltsthereof.

The compounds of formula (I) for which R₁ is methyl or hexyl and R₂ ishydrogen or else R₁ and R₂ are methyl are known as chemical products (J.Org. Chem., 27, 1049 (1962); J. Org. Chem., 37, 4401 (1972); BeilsteinRegistry Numbers 6114855, 6114856, 6117694, 6117695).

Moreover, certain compounds of formula (I) are known as radioprotectiveagents. These are the racemic compounds for which

R₁ is a methyl radical and R₂ is a hydrogen atom (Chem. Abst., 1980, 92,209060 and 209061),

R₁ is hydrogen and R₂ is methyl (Chem. Abst., 1997, 87, 193910),

R₁ is hydrogen and R₂ is ethyl (Khim. Geterotsikl. Soedin, 1987, 11,1572),

R₁ is hydrogen and R₂ is n-propyl (Radiobiologiya, 1979, 19 (5), 671).

The other compounds of formula (I) are novel and, as such, they formpart of the invention, as do the racemic mixtures, enantiomers,diastereoisomers and tautomers thereof and the pharmaceuticallyacceptable salts thereof.

These are the compounds for which either R₁ is a hydrogen atom or analkyl radical and R₂ is an alkyl, -alk-NH₂, —CH₂—R₃ or —CH₂—S—R₄ radicalor a phenyl radical substituted with a nitro or —NH—C(═NH)CH₃ radical,

or R₁ is an alkyl radical and R₂ is a hydrogen atom,

R₃ is a cycloalkyl (3-6C), pyridyl, thienyl, thiazolyl, imidazolyl,pyrazinyl, triazolyl or phenyl radical or a phenyl radical substitutedwith a nitro, hydroxyl or carboxyl radical,

R₄ represents a pyridyl radical,

alk represents an alkylene radical,

the racemic mixtures, enantiomers and diastereoisomers thereof andmixtures thereof, the tautomers thereof and the pharmaceuticallyacceptable salts thereof,

with the exception of the compounds for which R₁ is hexyl or methyl andR₂ is hydrogen or else R₁ and R₂ are methyl, and the racemic mixtures ofthe compounds for which R₁ is hydrogen and R₂ is methyl, ethyl orn-propyl.

The compounds of formula (I) that are particularly preferred are thosefor which R₁ is a hydrogen atom or an alkyl radical and R₂ is an-alk-NH₂ radical, a phenyl radical substituted with an —NH—C(═NH)CH₃radical, a radical —CH₂—R₃ for which R₃ is a pyridyl, thienyl,thiazolyl, imidazolyl, triazolyl, pyrazinyl or phenyl radical or aphenyl radical substituted with a nitro or carboxyl radical, or aradical —CH₂—S—R₄ for which R₄ is a pyridyl radical, the racemicmixtures, enantiomers and diastereoisomers thereof and mixtures thereof,the tautomers thereof and the pharmaceutically acceptable salts thereof.

In particular, R₃ is a 3- or 4-pyridyl, 2- or 3-thienyl, 4- or5-thiazolyl, 1-imidazolyl, 1-triazolyl, 2-pyrazinyl or phenyl radical ora phenyl radical substituted in position −3 with a nitro or carboxylradical and R₄ is a 4-pyridyl radical.

Among the novel compounds of formula (I) which may be mentioned are thefollowing compounds:

4-(3-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

4-(3-nitrobenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine

4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine

4-(3-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

4-(2-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

5-methyl-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol -2-ylamine

5-ethyl-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

4-(4-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

4-(1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

4-(2-pyrazinylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

4-(5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

4-(1-triazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

4-(4-pyridylsulphanylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

the racemic mixtures, enantiomers, diastereoisomers and tautomersthereof and the pharmaceutically acceptable salts thereof, and inparticular the following compounds:

(+)-(4R)-4-(3-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

(+)-(4R)-4-(3-nitrobenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine

(+)-(4R,5S)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine

(+)-(4R,5R)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine

(−)-(4R)-4-(3-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

(4R)-4-(2-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

[3-(2-amino-4,5-dihydrothiazol-4-yl)phenyl](1-imino-ethyl)amine

(+)-(4R)-4-benzyl-4,5-dihydro-1,3-thiazol-2-ylamine

(+)-(4R)-4-(3-carboxybenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine

(+)-(4R)-4-(4-aminobutyl)-4,5-dihydro-1,3-thiazol-2-ylamine

(−)-(4S)-4-(3-nitrobenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine

(−)-(4S,5S)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine

(−)-(4S)-4-(4-aminobutyl)-4,5-dihydro-1,3-thiazol-2-ylamine

(4S,5R)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine

(+)-(4R)-4-(4-pyridylmethyl-4,5-dihydro-1,3-thiazol-2-ylamine

(+)-(4R,5R)-5-methyl-4-(4-pyridylmethyl-4,5-dihydro-1,3-thiazol-2-ylamine

(+)-(4R,5R)-5-ethyl-4-(4-pyridylmethyl-4,5-dihydro-1,3-thiazol-2-ylamine

(4S,5R)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine

(+)-(4R)-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

(+)-(4R,5R))-5-methyl)-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

(+)-(4R,5R))-5-ethyl)-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

(+)-4-(5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

(−)-4-(5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

(+)-(4R)-4-(2-pyrazinylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

(4R)-4-(1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

(4S)-4-(1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

(+)-(4R)-4-(4-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

(+)-4-(4-pyridylsulphanylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

(+)-4-(1-triazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine

the tautomers thereof and the pharmaceutically acceptable salts thereof.

The invention also relates to pharmaceutical compositions containing, asactive principle, a derivative of formula (I) for which

either R₁ is a hydrogen atom or an alkyl radical and R₂ is an alkyl,-alk-NH₂, —CH₂—R₃ or —CH₂—S—R₄ radical or a phenyl radical substitutedwith a nitro or —NH—C(═NH)CH₃ radical,

or R₁ is an alkyl radical and R₂ is a hydrogen atom,

R₃ is a cycloalkyl (3-6C), pyridyl, thienyl, thiazolyl, imidazolyl,pyrazinyl, triazolyl or phenyl radical or a phenyl radical substitutedwith a nitro, hydroxyl or carboxyl radical,

R₄ represents a pyridyl radical and alk represents an alkylene radical,

as well as the racemic mixtures, enantiomers and diastereoisomersthereof and mixtures thereof, the tautomer thereof and thepharmaceutically acceptable salts thereof,

with the exception of the racemic compounds for which R₁ is a methylradical and R₂ is a hydrogen atom or else R₁ is hydrogen and R₂ ismethyl, ethyl or n-propyl.

The compounds of formula (I) can be prepared by cyclization of aderivative of formula:

in which R₁ and R₂ have the same meanings as in formula (I).

This cyclization is generally carried out using an acid such ashydrochloric acid, in aqueous medium, at a temperature of 100° C. 6Nhydrochloric acid is preferably used.

The derivatives of formula (II) can be obtained according to thefollowing reaction schemes: Scheme 1 for the compounds for which R₁ ishydrogen

in these formulae R₂ has the same meanings as in formula (I), Ra is ahydrogen atom or a protecting group for the amine function, such asthose described by T. W. Greene, Protective groups in organic synthesis,J. Wiley-Interscience Publication (1991) and Rb is a (1-4C) alkyl oralkoxycarbonyl radical, preferably methyl, ethyl or isobutyloxycarbonyl.The protecting group for the amine function is preferably an acetyl ortert-butoxycarbonyl radical.

Reaction a is generally carried out in the presence of a sodium (1-4C)alkoxide (preferably sodium ethoxide), in the corresponding alcohol, ata temperature of between 10° C. and the boiling point of the reactionmedium.

Reaction b is generally carried out in an inert solvent such asdimethylformamide in the presence of lithium iodide, at a temperature ofbetween 100° C. and the boiling point of the reaction medium, or in a(1-4C) aliphatic alcohol, in the presence of sodium hydroxide, at atemperature from 10° C. to 30° C., followed by neutralizing with 6N HClthen heating in a solvent such as dioxane at a temperature in the regionof 100° C.

Reaction b′ is preferably carried out using hydrochloric acid, at atemperature of 100° C.

Reaction b″ for the derivatives for which Rb is an alkyl radical isgenerally carried out by the action of a (1-4C) aliphatic alcohol(preferably methanol or ethanol), in the presence of an inorganic acidsuch as sulfuric acid, at a temperature of between 50° C. and theboiling point of the reaction medium. For the derivatives for which Rbis an isobutyloxycarbonyl radical, this reaction is generally carriedout by the action of isobutyl chloroformate in the presence of a basesuch as triethylamine, in an inert solvent such as tetrahydrofuran, at atemperature of between −20° C. and 0° C.

The reduction reactions c, g and i are preferably carried out using ahydride such as sodium borohydride or lithium aluminum hydride, in a(1-4C) aliphatic alcohol or tetrahydrofuran, at a temperature of between10° C. and 30° C., or alternatively using a borane derivative such asthe BH₃-THF complex, in a solvent such as tetrahydrofuran, at atemperature of between 0° C. and 30° C.

The deprotection reaction d for the compounds for which Ra is aprotecting group for the amine function is carried out by anydeprotection method known to those skilled in the art, and in particularthose described by T. W. Greene, Protective groups in organic synthesis,J. Wiley-Interscience Publication (1991). Preferably, when theprotecting group is an acetyl radical, this reaction is carried outusing aqueous hydrochloric acid, at a temperature of 100° C. When theprotecting group is a tert-butoxycarbonyl radical, this reaction iscarried out using hydrochloric acid in dioxane, at a temperature in theregion of 20° C.

Reactions e and h are carried out by the action of tert-butylisothiocyanate, in an inert solvent such as a (1-4C) aliphatic alcohol(preferably methanol or ethanol), optionally in the presence of atertiary amine such as triethylamine, at a temperature of between 20° C.and the boiling point of the reaction medium.

Reaction f is carried out by the action of a (1-4C) aliphatic alcohol(preferably methanol or ethanol), in the presence of an inorganic acidsuch as hydrochloric acid, at a temperature of between 20° C. and theboiling point of the reaction medium, or alternatively by the action ofthionyl chloride, in a (1-4C) aliphatic alcohol (preferably methanol orethanol), at a temperature of between 25° C. and 30° C. Scheme 2 for thecompounds for which R₁ is alkyl

in these formulae R₁ and R₂ have the same meanings as in formula (I), Rais a hydrogen atom or a protecting group for the amine function, such asthose described by T. W. Greene, Protective groups in organic synthesis,J. Wiley-Interscience Publication (1991) and preferably an acetyl ortert-butoxycarbonyl radical, and Rb is an alkyl or alkoxycarbonylradical, and preferably methyl, ethyl or isobutyloxycarbonyl.

Reaction a is preferably carried out in an inert solvent such as achlorinated solvent (for example chloroform or dichloromethane),optionally in the presence of a base such as N-methylmorpholine ortriethylamine, at a temperature of between −15° C. and 30° C.

Reaction b is carried out by the action of an alkylmagnesium halide suchas an alkylmagnesium bromide, in an ether such as tetrahydrofuran orethyl ether, at a temperature of between 0° C. and 30° C.

The reduction reaction c is preferably carried out using a hydride suchas sodium borohydride or lithium aluminum hydride, in a (1-4C) aliphaticalcohol or tetrahydrofuran, at a temperature of between 10° C. and 30°C., or using a borane derivative such as the BH₃-THF complex, in asolvent such as tetrahydrofuran, at a temperature of between 0° C. and30° C.

The deprotection reaction d is carried out by any method known to thoseskilled in the art for deprotecting an amine function, and in particularthose described by T. W. Greene, Protective groups in organic synthesis,J. Wiley-Interscience Publication (1991). Preferably, when theprotecting group is an acetyl radical, this reaction is carried outusing aqueous hydrochloric acid, at a temperature of 100° C. When theprotecting group is a tert-butoxycarbonyl radical, this reaction iscarried out using hydrochloric acid in dioxane, at a temperature in theregion of 20° C.

Reaction e is carried out by the action of tert-butyl isothiocyanate, inan inert solvent such as a (1-4C) aliphatic alcohol (preferably methanolor ethanol), in the presence of a tertiary amine such as triethylamine,at a temperature of between 20° C. and the boiling point of the reactionmedium.

The compounds of formula (I) for which R₂ is a phenyl radicalsubstituted with an —NH—C(═NH)CH₃ radical can also be prepared from thecorresponding amine derivatives which are themselves obtained byreducing the nitro derivatives of formula (I) according to the followingscheme:

The reduction reaction a is carried out by any reduction method known tothose skilled in the art for proceeding from a nitro to an amino withoutaffecting the rest of the molecule. The process is preferably performedusing zinc, in acetic acid, at a, temperature in the region of 20° C.

Reaction b is carried out by reaction of benzyl ethanimidothioatehydrochloride, in an inert solvent such as a (1-4C) aliphatic alcoholand preferably methanol or ethanol, at a temperature of between 0° C.and 45° C.

The intermediates of formula (III) are novel and form part of theinvention.

The compounds of formula (I) for which R₂ is a radical —CH₂—R₃ in whichR₃ is a 1-imidazolyl or 1-(1,2,4-triazolyl) radical may also be preparedby the action of imidazolyl or of 1,2,4-triazole on a derivative offormula:

in which R₁ has the same meanings as in formula (I), X is a halogenatom, and in particular an iodine atom, or a tosyl radical, Ra and Rbare hydrogen atoms or protecting groups for the amine function such asthose described by T. W. Greene, Protective Groups in Organic Synthesis,J. Wiley-Interscience Publication (1991), preferably alkoxycarbonyl oracetyl and more particularly tert-butoxycarbonyl, optionally followed bya deprotection.

This reaction is generally carried out in the presence of a base such asan alkali metal hydride, preferably sodium hydride, in a solvent such asdimethyl sulfoxide, at a temperature of between 20° C. and the boilingpoint of the reaction medium.

The deprotection reaction for the compounds for which Ra or Rb is aprotecting group for the amine function is carried out by anydeprotection method known to those skilled in the art and in particularthose described by T. W. Greene, Protective Groups in Organic Synthesis,J. Wiley-Interscience Publication (1991). Preferably, when theprotecting group is an acetyl radical, this reaction is carried outusing aqueous hydrochloric acid, at a temperature of 100° C. When theprotecting group is a tert-butoxycarbonyl radical, this reaction iscarried out using hydrochloric acid in dioxane, at a temperature in theregion of 20° C.

The compounds of formula (IV) may themselves be obtained according tothe following reaction scheme:

In these formulae, R₁ has the same meaning as in formula (I), Ts is atosylate radical, Ra and Rb are a hydrogen atom or a protecting groupfor the amine function such as those described by T. W. Greene,Protective Groups in Organic Synthesis, J. Wiley-IntersciencePublication (1991), preferably alkoxycarbonyl or acetyl and moreparticularly tert-butoxycarbonyl.

Reaction a is generally carried out by the action of tert-butylisothiocyanate, in an inert solvent such as an aliphatic alcohol (1-4C)(preferably methanol or ethanol), optionally in the presence of atertiary amine such as triethylamine, at a temperature of between 20° C.and the boiling point of the reaction medium.

Cyclization reaction b is generally carried out using an acid such ashydrochloric acid, in aqueous medium, at a temperature in the region of100° C. 6N hydrochloric acid is preferably used.

When Ra or Rb is a tert-butoxycarbonyl group, reactions c and g arecarried out by any protection method known to those skilled in the artand in particular those described by T. W. Greene, Protective Groups inOrganic Synthesis, J. Wiley-Interscience Publication (1991). Thisreaction is preferably carried out using di-tert-butyl dicarbonate, inthe presence of a base such as triethylamine and optionally in thepresence of 4-(dimethylamino)pyridine, in a solvent such asdichloromethane and at a temperature in the region of 20° C., oralternatively in the presence of a base such as potassium carbonate, ina solvent such as water and at a temperature in the region of 20° C.

Reaction d is generally carried out by the action of p-toluenesulfonylchloride, in the presence of a tertiary amine such as triethylamine, inan inert solvent such as dichloromethane, at a temperature of between20° C. and the boiling point of the reaction medium.

Reaction e is generally carried out by the action of sodium iodide, inan inert solvent such as acetone, at a temperature of between 20° C. andthe boiling point of the reaction medium.

Reaction f is generally carried out by the action of an allyl halide,for example allyl chloride, in an aliphatic alcohol (1-4C), preferablyethanol, at a temperature of between 20° C. and the boiling point of thereaction medium.

Reaction h is generally carried out by the action of iodine, in thepresence of base such as sodium bicarbonate, in a solvent such asdichloromethane, at a temperature of between 20° C. and the boilingpoint of the reaction medium.

The compounds of formula (I) for which R₂ is a radical —CH₂—S—R₄ may beprepared by the action of a corresponding compound of formula (IVa) or(IVb) with a derivative of formula HS-R₄ in which R₄ has the samemeaning as in formula (I) and Ra and Rb are hydrogen atoms or protectinggroups for the amine function such as those described by T. W. Greene,Protective Groups in Organic Synthesis, J. Wiley-IntersciencePublication (1991), preferably alkoxycarbonyl or acetyl and moreparticularly tert-butoxycarbonyl, optionally followed by a deprotectionof the amine function.

This reaction is generally carried out in the presence of a base such aspotassium carbonate, in a solvent such as acetonitrile ordimethylformamide (preferably acetonitrile), at a temperature of between20° C. and the boiling point of the reaction medium.

The deprotection reaction for the compounds for which Ra or Rb is aprotecting group for the amine function is carried out by anydeprotection method known to those skilled in the art and in particularthose described by T. W. Greene, Protective Groups in Organic Synthesis,J. Wiley-Interscience Publication (1991). Preferably, when theprotecting group is an acetyl radical, this reaction is carried outusing aqueous hydrochloric acid, at a temperature of 100° C. When theprotecting group is a tert-butoxycarbonyl radical, this reaction iscarried out using hydrochloric acid in dioxane, at a temperature in theregion of 20° C. The compounds of formula (I) are isolated and may bepurified by the usual known methods, for example by crystallization,chromatography or extraction.

The enantiomers of the compounds of formula (I) can be obtained byresolving the racemic mixtures, for example by chromatography on achiral column according to Pirckle W. H. et al., Asymmetric Synthesis,Vol. 1, Academic Press (1983) or by formation of salts or by synthesisfrom chiral precursors. The diastereoisomers can be prepared accordingto the known conventional methods (crystallization or chromatography orfrom chiral precursors).

The compounds of formula (I) can optionally be converted into additionsalts with an inorganic or organic acid by the action of such an acid inan organic solvent such as an alcohol, a ketone, an ether or achlorinated solvent. These salts also form part of the invention.

Examples of pharmaceutically acceptable salts which may be mentioned arethe following salts: benzenesulfonate, hydrobromide, hydrochloride,citrate, ethanesulfonate, fumarate, gluconate, iodate, isethionate,maleate, methanesulfonate, methylenebis-β-oxynaphthoate, nitrate,oxalate, pamoate, phosphate, salicylate, succinate, sulfate, tartrate,theophyllineacetate and p-toluenesulfonate.

The compounds of formula (I) are inhibitors of inducible NO-synthase ortype-2 NO-synthase (NOS-2) and are thus useful for preventing andtreating disorders associated with excessive NO production, such asmultiple sclerosis, cerebral, focal or global ischemia, cerebral orspinal trauma, Parkinson's disease, Huntington's disease, Alzheimer'sdisease, amiotrophic lateral sclerosis, migraine, depression,schizophrenia, anxiety and epilepsy, diabetes, atherosclerosis,myocarditis, arthritis, arthrosis, asthma, irritable bowel syndrome,Crohn's disease, peritonitis, gastro-esophageal reflux, uveitis,Guillain-Barré syndrome, glomerulonephritis, lupus erythematosus,psoriasis, the growth of certain forms of tumors such as, for example,epitheliomas, adenocarcinomas or sarcomas, and infections withGram-positive or Gram-negative intracellular or extracellular bacteria.

Their activities as NOS-2 and NOS-3 inhibitors were determined bymeasuring the conversion of [³H]-L-arginine into [³H]-L-citrulline with,respectively, an NOS-2 enzymatic fraction extracted from the lungs ofrats or mice pretreated with lipopolysaccharides (10 mg/kg i.p. 6 hoursbefore collecting the tissue) and with a commercial preparation ofrecombinant bovine NOS-3. The compounds were incubated for 20 to 30minutes at 37° C. in the presence of 5 μM (for NOS-2 activity) or 10 μM(for NOS-3 activity) of [³H]-L-arginine, 1 mM of NADPH, 15 μM oftetrabiopterine, 1 μM of FAD, 0.1 mM of DTT in a HEPES buffer (50 mM, pH6.7) containing 10 μg/ml of calmodulin and 1.25 mM of CaCl₂ when theNOS-3 activity was measured. The incubation was stopped by adding coldHEPES buffer (100 mM, pH 5.5) containing 10 mM of EGTA and 500 mg of acationic ion-exchange resin (AG50W-X8, counterion: Na⁺) to separate the[³H]-L-arginine from the [³H]-L-citrulline. After separation of thephases by settling for 5 min, the radioactivity remaining in the liquidphase was measured in a scintillation counter in the presence of asuitable scintillation liquid. The yield for the recovery of the[³H]-L-citrulline formed was able to be estimated using[¹⁴C-ureido]-L-citrulline as external standard. The NOS-2 or NOS-3activity was expressed in picomole(s) of [³H]-L-citrulline formed perminute and per milligram of protein contained in the reaction medium.

In this test on the enzyme NOS-2, the IC₅₀ value for the compounds offormula (I) is less than or equal to 10 μM.

The selectivity is measured by the NOS-3 IC₅₀/NOS-2 IC₅₀ ratio. Thisselectivity is greater than 20.

The compounds of formula (I) are of low toxicity. Their LD₅₀ value isgreater than 40 mg/kg via the cutaneous route in mice.

The examples which follow illustrate the invention.

EXAMPLE 1 (+)-(4R)-4-(3-Pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylaminedihydrochloride

A suspension of 3.35 g ofN-(tert-butyl)-N′-[(1R)-2-hydroxy-1-(3-pyridylmethyl)ethyl]thiourea in32 cm³ of 6N hydrochloric acid is heated at a temperature in the regionof 100° C. for 5 hours and the heating is then stopped. The solution isthen evaporated under reduced pressure (2 kPa) at a temperature in theregion of 50° C. 4.42 g of a yellow oil which becomes pasty areobtained. This paste is taken up in acetone and then re-evaporated underreduced pressure (2 kPa) at a temperature in the region of 40° C. Theresidue is taken up in diethyl ether. Light beige-colored crystals areobtained, and are filtered off on a sinter funnel and then washed withdiethyl ether and dried in an oven under reduced pressure (0.1 kPa) at atemperature in the region of 50° C. 3.28 g of(+)-(4R)-4-(3-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylaminedihydrochloride are obtained in the form of a light beige-colored sandysolid melting at 124° C. [¹H NMR spectrum (300 MHz, (CD₃)₂SO-d₆, δ inppm): 3.20 (mt: 2H); 3.40 (dd, J=11 and 5 Hz: 1H); 3.70 (dd, J=11 and 8Hz: 1H); 4.67 (mt: 1H); 7.97 (dd, J=8 and 5.5 Hz: 1H); 8.46 (broad d,J=8 Hz: 1H); 8.83 (broad d, J=5.5 Hz: 1H); 8.90 (d, J=2 Hz: 1H); 9.28(unres. mult.: 1H); 9.75 (unres. mult.: 1H); 10.30 (unres. mult.: 1H);(α_(D) ²⁰=+18.3±0.7 at a concentration of 0.5% in methanol)].

N-(tert-Butyl)-N′-[(1R)-2-hydroxy-1-(3-pyridylmethyl)ethyl]thiourea:22.7 cm³ of triethylamine and then 14 cm³ of tert-butyl isothiocyanateare added dropwise to a suspension, under an inert atmosphere, of 16.51g of (2R)-2-amino-3-(3-pyridyl)-1-propanol dihydrochloride in 200 cm³ ofethanol. The mixture is then heated at a temperature in the region of60° C. for 1 hour 30 min. After cooling to a temperature in the regionof 20° C., the insoluble material is filtered off on a sinter funnel andthe filtrate is then evaporated under reduced pressure (2 kPa) at atemperature in the region of 40° C. A yellow paste is obtained, and istaken up in 200 cm³ of ethyl acetate and 100 cm³ of water. The aqueousphase is extracted and then washed with twice 200 cm³ of ethyl acetate.The organic phases are combined, washed with 3 times 50 cm³ of saturatedsodium chloride solution and dried over magnesium sulfate. Afterfiltration and then evaporation under reduced pressure (2 kPa) at atemperature in the region of 40° C., a yellow oil is obtained, which istaken up in dichloromethane and re-evaporated to give 3.25 g ofN-(tert-butyl)-N′-[(1R)-2-hydroxy-1-(3-pyridylmethyl)-ethyl]thiourea inthe form of a pale yellow foam: [¹H NMR spectrum (400 MHz, (CD₃)₂SO-d₆,δ in ppm): 1.41 (s: 9H); 2.84 (mt: 2H); 3.37 (mt: 2H); 4.43 (unres.mult.: 1H); 4.96 (t, J=5 Hz: 1H); 7.24 (d, J=8 Hz: 1H); 7.27 (broad s:1H); 7.33 (dd, J=8 and 5 Hz: 1H); 7.67 (dt, J=8 and 2 Hz: 1H); 8.42 (dd,J=5 and 2 Hz: 1H); 8.46 (d, J=2 Hz: 1H)].

(2R)-2-Amino-3-(3-pyridyl)-1-propanol dihydrochloride: A suspension of13.55 g of N-[(1R)-2-hydroxy-1-(3-pyridylmethyl)ethyl]acetamide in 110cm³ of aqueous 6N hydrochloric acid is heated at a temperature in theregion of 100° C. for 3 hours. The water is evaporated off under reducedpressure (3 kPa) at a temperature in the region of 50° C. 16.51 g of(2R)-2-amino-3-(3-pyridyl)-1-propanol dihydrochloride are obtained inthe form of an off-white solid. [¹H NMR spectrum (400 MHz, (CD₃)₂SO-d₆,δ in ppm): 3.13 (d, J=7.5 Hz: 2H); 3.50 (mt: 2H); 3.62 (mt: 1H); 7.94(dd, J=8 and 5.5 Hz: 1H); 8.27 (unres. mult.: 3H); 8.43 (broad d, J=8Hz: 1H); 8.79 (broad d, J=5.5 Hz: 1H); 8.86 (broad s: 1H)].

N-[(1R)-2-Hydroxy-1-(3-pyridylmethyl)ethyl]-acetamide: A solution, underan inert atmosphere, of 20.77 g of ethyl(2R)-2-(acetylamino)-3-(3-pyridyl)propanoate in 208 cm³ of anhydrousethanol is cooled to a temperature in the region of 10° C., followed byportionwise addition of 8.31 g of sodium borohydride. The reactionmixture is stirred for 16 hours at room temperature. The ethanol isevaporated off under reduced pressure (2 kPa) at a temperature in theregion of 40° C., to give 43.56 g of a pale yellow paste which is takenup and stirred in 50 cm³ of water. The solution, which has a pH in theregion of 12, is cooled to a temperature in the region of 0° C. and thenneutralized by dropwise addition of concentrated hydrochloric acid. Theresulting mixture is stirred for 1 hour at this temperature and thewhite precipitate formed is then filtered off on a sinter funnel, thendried in an oven under vacuum (0.1 kPa) at a temperature in the regionof 55° C. 11.15 g ofN-[(1R)-2-hydroxy-1-(3-pyridylmethyl)ethyl]acetamide are obtained in theform of a white solid melting at a temperature above 260° C. Thefiltrate is extracted with 3 times 100 cm³ of ethyl acetate and theorganic phases are then combined, dried over magnesium sulfate, filteredand evaporated under reduced pressure (2 kPa) at a temperature in theregion of 40° C. 2.4 g ofN-[(1R)-2-hydroxyl-1-(3-pyridylmethyl)ethyl]acetamide partiallycomplexed with boron are obtained in the form of a white paste. [¹H NMRspectrum (300 MHz, (CD₃)₂SO-d₆, δ in ppm): 1.75 (s: 3H); 2.61 (dd, J=14and 9 Hz: 1H); 2.88 (dd, J=14 and 5.5 Hz: 1H); from 3.20 to 3.45 (mt:2H); 3.91 (mt: 1H); 4.82 (broad t, J=5 Hz: 1H); 7.30 (dd, J=7.5 and 5Hz: 1H); 7.62 (dt, J=7.5 and 2 Hz: 1H); 7.72 (d, J=9 Hz: 1H); from 8.35to 8.45 (mt: 2H)].

Ethyl (2R)-2-(acetylamino)-3-(3-pyridyl)propanoate: A suspension of 54.7g of ethyl 2-(acetylamino)-3-(3-pyridyl)propanoate in 420 cm³ of water,to which has been added 18.5 g of potassium chloride, is dissolved byadding 100 cm³ of acetonitrile. An orange-colored solution of neutral pHis obtained, 0.168 g of α-chymotrypsin is then added and the pH falls.Aqueous 2N potassium hydroxide solution is added dropwise, withstirring, to remain at a constant pH of 7.2. After 1 hour 30 min, withthe pH showing little change, the mixture is stirred for 48 hours atroom temperature. The pH of the solution is then approximately 5.6 and,on adding aqueous 2N potassium hydroxide solution, it is therebyadjusted to about 7. 0.084 g of α-chymotrypsin is introduced and the pHis adjusted to 7.2 by a further addition of aqueous 2N potassiumhydroxide solution, and the mixture is left stirring for 1 hour 30 min.The pH of the reaction medium does not change. 400 cm³ of ethyl acetateare added and the mixture is stirred for 30 min and then filteredthrough Celite. The filtrate is separated out after settling has takenplace and the aqueous phase is extracted with 3 times 400 cm³ of ethylacetate. The organic phases are combined, washed with 400 cm³ ofsaturated sodium chloride solution and dried over magnesium sulfate.After filtration and concentration under reduced pressure (2 kPa) at atemperature in the region of 40° C., 20.77 g of ethyl(2R)-2-(acetylamino)-3-(3-pyridyl)propanoate are obtained in the form ofa beige-colored solid melting at 80° C. [¹H NMR spectrum (400 MHz,(CD₃)₂SO-d₆, δ in ppm): 1.13 (t, J=7 Hz: 3H); 1.81 (s: 3H); 2.92 (dd,J=14 and 9.5 Hz: 1H); 3.05 (dd, J=14 and 5.5 Hz: 1H); 4.07 (q, J=7 Hz:2H); 4.48 (mt: 1H); 7.33 (dd, J=8 and 5 Hz: 1H); 7.66 (dt, J=8 and 2 Hz:1H); 8.36 (d, J=8 Hz: 1H); 8.44 (mt: 2H)].

Ethyl 2-(acetylamino)-3-(3-pyridyl)-propanoate: 44.45 cm³ of aqueous 6Nsodium hydroxide are added dropwise to a solution of 51.4 g of diethyl2-(acetylamino)-2-(3-pyridylmethyl)malonate in 857 cm³ of ethanol. Themixture is stirred for 1 hour 30 minutes at a temperature in the regionof 20° C. and then cooled to a temperature in the region of 0° C. 22.2cm³ of 12N hydrochloric acid are added dropwise; a precipitate forms.The reaction medium is warmed to room temperature and, after stirringfor 2 hours, its pH is 5-6. It is concentrated under reduced pressure (4kPa) at a temperature in the region of 50° C., to give a stickydark-beige solid which is dried for 16 hours in an oven under vacuum(0.1 kPa) at a temperature in the region of 50° C. This residue is takenup in 1000 cm³ of dioxane and then heated to a temperature in the regionof 100° C. for 1 hour. The dioxane is evaporated off under reducedpressure (2 kPa) at a temperature in the region of 40° C., and theresidue is dissolved in 250 cm³ of water. This solution is neutralizedby addition of 4 cm³ of aqueous 10N sodium hydroxide, followed byaddition of 750 cm³ of ethyl acetate. After separation of the phases bysettling, the organic phase is extracted and the aqueous phase is washedwith twice 300 cm³ of ethyl acetate. The organic phases are combined,dried over magnesium sulfate, filtered and concentrated under reducedpressure (2 kPa) at a temperature in the region of 40° C. The solidresidue obtained is taken up in 70 cm³ of ethyl acetate and 20 cm³ ofheptane and then filtered on a sinter funnel. 27.76 g of ethyl2-(acetylamino)-3-(3-pyridyl)propanoate are obtained in the form of abeige-colored solid melting at 118° C. [¹H NMR spectrum (400 MHz,(CD₃)₂SO-d₆, δ in ppm): 1.13 (t, J=7 Hz: 3H); 1.81 (s: 3H); 2.92 (dd,J=14 and 9 Hz: 1H); 3.04 (dd, J=14 and 5.5 Hz: 1H); 4.07 (q, J=7 Hz:2H); 4.48 (mt: 1H); 7.33 (dd, J=8 and 5 Hz: 1H); 7.66 (dt, J=8 and 2 Hz:1H); 8.38 (d, J=8 Hz: 1H); 8.45 (mt: 2H)]. By re-extracting the aqueousphase with twice 500 cm³ of ethyl acetate and after drying andconcentration of the combined organic phases under reduced pressure, 4 gof ethyl 2-(acetylamino)-3-(3-pyridyl)propanoate are recovered in theform of a beige-yellow solid melting at 121° C.

In the same way, starting with 50.2 g of diethyl2-(acetylamino)-2-(3-pyridylmethyl)malonate, 26.94 g of ethyl2-(acetylamino)-3-(3-pyridyl)-propanoate are obtained.

Diethyl 2-(acetylamino)-2-(3-pyridylmethyl)-malonate: 17.2 g of sodiumprewashed twice with pentane are added portionwise, with stirring underan inert atmosphere, to 600 cm³ of ethanol. After total consumption ofthe sodium, 73.5 g of diethyl acetamidomalonate are added rapidly andthe mixture is left stirring for 30 min at a temperature in the regionof 40° C. A suspension of 56 g of 3-picolyl chloride hydrochloride in300 cm³ of ethanol is then added rapidly and the resulting pinkishsuspension is stirred for 44 hours at a temperature in the region of 20°C. 28.1 g of potassium iodide are added and stirring is continued atroom temperature for 4 hours, and the reaction mixture is finally heatedat a temperature in the region of 50° C. for 44 hours. The mixture iscooled to a temperature in the region of 0° C. and then filtered througha sinter funnel to remove the salts, which are washed with ethanol. Thefiltrate is concentrated under reduced pressure (2 kPa) at a temperaturein the region of 40° C. A brown-colored paste is obtained, and isdissolved in 100 cm³ of water and treated with 7 cm³ of aqueous 3Nhydrochloric acid until a pH in the region of 6 is obtained. The mixtureis placed in a refrigerator for 48 hours. The crystalline precipitateobtained is filtered off on a sinter funnel, washed with 50 cm³ ofice-cold water, spin-filtered and then dried in a desiccator underreduced pressure (5 kPa) for 16 hours. After drying in an oven underreduced pressure (0.1 kPa) at a temperature in the region of 40° C. for4 hours, 50.2 g of diethyl 2-(acetylamino)-2-(3-pyridylmethyl)malonateare obtained in the form of a dark beige-colored solid melting at 96° C.[¹H NMR spectrum (400 MHz, (CD₃)₂SO-d₆, δ in ppm) 1.19 (t, J=7 Hz: 6H);1.97 (s: 3H); 3.47 (s: 2H); 4.17 (q, J=7 Hz: 4H); 7.33 (dd, J=8 and 5Hz: 1H); 7.41 (dt, J=8 and 2 Hz: 1H); 8.21 (d, J=2 Hz: 1H); 8.24 (s:1H); 8.24 (s: 1H); 8.47 (dd, J=5 and 2 Hz: 1H)].

EXAMPLE 2 (+)-(4R)-4-(3-Nitrobenzyl)-4,5-dihydro-1,3-thiazol-2-ylaminehydrochloride

1.1 g ofN-(tert-butyl)-N′-[(1R)-2-hydroxy-1-(3-nitrobenzyl)ethyl]thiourea in 12cm³ of 6N hydrochloric acid are heated for 5 hours at a temperature inthe region of 100° C. The reaction medium is then cooled to atemperature in the region of 0° C.; a white precipitate forms, which isfiltered off on a sinter funnel and then washed with 3 times 20 cm³ ofdiethyl ether. The filter cake is then dried in a desiccator undervacuum. 0.68 g of(+)-(4R)-4-(3-nitrobenzyl)-4,5-dihydro-1,3-thiazol-2-ylaminehydrochloride is obtained in the form of beige-colored crystals meltingat 232° C. [¹H NMR spectrum (300 MHz, (CD₃)₂SO-d₆, δ in ppm): 3.15(limiting AB: 2H); from 3.25 to 3.45 (mt: 1H); 3.63 (dd, J=13 and 8 Hz:1H); 4.62 (mt: 1H); 7.68 (t, J=8 Hz: 1H); 7.81 (broad d, J=8 Hz: 1H);8.18 (broad d, J=8 Hz: 1H); 8.24 (broad s: 1H); from 9.00 to 10.40(unres. mult.: 3H); (α_(D) ²⁰=+18.8±0.6 at a concentration of 0.5% inmethanol)].

N-(tert-Butyl)-N′-[(1R)-2-hydroxy-1-(3-nitrobenzyl)ethyl]thiourea: Asuspension of 0.92 g of (2R)-2-amino-3-(3-nitrophenyl)-1-propanolhydrochloride and 0.6 cm³ of tert-butyl isothiocyanate in 10 cm³ ofethanol is cooled to a temperature in the region of 0° C. and 0.56 cm³of triethylamine is then added. The mixture is stirred for 18 hours atroom temperature and is then heated at a temperature in the region of60° C. for 2 hours; the suspension thus dissolves. 0.6 cm³ of tert-butylisothiocyanate is added and heating is continued for 3 hours, afterwhich the reaction medium is concentrated under reduced pressure (2 kPa)at a temperature in the region of 50° C. The yellow oil obtained isdissolved in 50 cm³ of ethyl acetate, after which the organic solutionis washed with twice 50 cm³ of sodium chloride solution, dried oversodium sulfate, filtered and concentrated under reduced pressure (2 kPa)at a temperature in the region of 40° C. 1.2 g ofN-(tert-butyl)-N′-[(1R)-2-hydroxy-1-(3-nitrobenzyl)-ethyl]thiourea areobtained in the form of a yellow oil. ¹H NMR spectrum (300 MHz,(CD₃)₂SO-d₆ with addition of a few drops of CD₃COOD-d₄, δ in ppm): 1.39(s: 9H); 2.98 (limiting AB: 2H); 3.38 (limiting AB: 2H); 4.48 (mt: 1H);7.60 (t, J=8 Hz: 1H); 7.74 (broad d, J=8 Hz: 1H); 8.09 (broad d, J=8 Hz:1H); 8.16 (broad s: 1H).

(2R)-2-Amino-3-(3-nitrophenyl)-1-propanol hydrochloride: A suspension of0.98 g of N-[(1R)-2-hydroxy-1-(3-nitrobenzyl)ethyl]acetamide in 10 cm³of 6N hydrochloric acid is heated at a temperature in the region of 100°C. for 10 hours (dissolution). The reaction medium is concentrated underreduced pressure (2 kPa) at a temperature in the region of 40° C. Theresidue is taken up in 20 cm³ of diethyl ether and re-evaporated underthe same conditions to give beige-colored crystals, which are washedwith 3 times 20 cm³ of diethyl ether and then filtered off on a sinterfunnel and finally dried in a fume cupboard. 0.92 g of(2R)-2-amino-3-(3-nitrophenyl)-1-propanol hydrochloride is obtained inthe form of beige-colored crystals melting at 192° C. [¹H NMR spectrum(250 MHz, (CD₃)₂SO-d₆, δ in ppm): 3.06 (limiting AB: 2H); from 3.25 to3.65 (mt: 3H); 5.45 (t, J=4.5 Hz: 1H); 7.65 (t, J=7 Hz: 1H); 7.79 (broadd, J=7 Hz: 1H); from 8.05 to 8.40 (mt: 5H)].

N-[(1R)-2-Hydroxy-1-(3-nitrobenzyl)ethyl]-acetamide: A light suspension,under an inert atmosphere, of 1.4 g of ethyl(2R)-2-(acetylamino)-3-(3-nitrophenyl)propanoate in 13 cm³ of ethanol iscooled to a temperature of 20° C. and 0.29 g of sodium borohydride isthen added thereto. The yellow solution obtained is stirred at roomtemperature for 18 hours. The reaction medium is then concentrated underreduced pressure (2 kPa) at a temperature in the region of 50° C., afterwhich 10 cm³ of water are added and the mixture is extracted with twice50 cm³ of ethyl acetate. The combined organic phases are dried oversodium sulfate, filtered and then concentrated under reduced pressure (2kPa) at a temperature in the region of 40° C. 1 g ofN-[(1R)-2-hydroxy-1-(3-nitrobenzyl)ethyl]-acetamide is obtained in theform of pale yellow crystals melting at 135° C. ¹H NMR spectrum (250MHz, (CD₃)₂SO-d₆, δ in ppm): 1.75 (s: 3H); 2.74 (dd, J=14 and 9 Hz: 1H);3.02 (dd, J=14 and 5 Hz: 1H); from 3.25 to 3.45 (mt: 2H); 3.96 (mt: 1H);4.90 (broad s: 1H); 7.59 (t, J=8 Hz: 1H); 7.70 (broad d, J=8 Hz: 1H);7.82 (d, J=8.5 Hz: 1H); from 8.05 to 8.15 (mt: 2H).

Ethyl (2R)-2-(acetylamino)-3-(3-nitrophenyl)-propanoate: A mixture of2.8 g of ethyl 2-(acetylamino)-3-(3-nitrophenyl)propanoate in 17 cm³ ofacetonitrile [lacuna] to which is added 3.95 g of ammonium hydrogencarbonate and 35 cm³ of water at a pH in the region of 8. 0.017 g oftype-II α-chymotrypsin is then introduced and the mixture is leftstirring at room temperature for 1 hour 15 min, while measuring the pHregularly. After this reaction time, the pH is less than 8, a further0.017 g of type-II α-chymotrypsin is added and stirring of the reactionmedium is continued for 2 hours 45 min. The aqueous phase is extractedwith 3 times 50 cm³ of ethyl acetate; the combined organic phases arethen dried over sodium sulfate, filtered and evaporated under reducedpressure (2 kPa) at a temperature in the region of 40° C. 1.4 g of ethyl(2R)-2-(acetylamino)-3-(3-nitrophenyl)propanoate are obtained in theform of white crystals melting at 110° C.

Ethyl 2-(acetylamino)-3-(3-nitrophenyl)-propanoate: 9.52 cm³ of aceticanhydride are added dropwise to 12 g of ethyl2-amino-3-(3-nitrophenyl)propanoate at a temperature in the region of 0°C. After stirring at 0° C. for 1 hour, the mixture sets to a solid. 10cm³ of acetic anhydride are then added and stirring is continued at 0°C. for a further 1 hour. The precipitate is filtered off on a sinterfunnel, washed with 3 times 25 cm³ of water and dried in a fume cupboardand then in an oven under vacuum (10 Pa) at a temperature in the regionof 50° C. 12 g of ethyl 2-(acetylamino)-3-(3-nitrophenyl)propanoate areobtained in the form of white crystals melting at 91° C. ¹H NMR spectrum(250 MHz, (CD₃)₂SO-d₆, δ in ppm): 1.14 (t, J=7 Hz: 3H); 1.80 (s: 3H);3.04 (dd, J=14 and 9 Hz: 1H); 3.18 (t, J=14 and 4 Hz: 1H); 4.08 (q, J=7Hz: 2H); 4.52 (mt: 1H); 7.61 (broad t, J=8 Hz: 1H); 7.72 (broad d, J=8Hz: 1H); 8.12 (mt: 2H); 8.42 (d, J=8.5 Hz: 1H).

Ethyl 2-amino-3-(3-nitrophenyl)propanoate: Gaseous hydrogen chloride isbubbled, to the saturation point, into a mixture of 23.4 g of3-nitrophenylalanine hydrochloride in 300 cm³ of ethanol cooled to atemperature in the region of 0° C. The suspension obtained is heated ata temperature in the region of 78° C. for 18 hours: this suspensiondissolves when hot. The heating is stopped and gaseous hydrogen chlorideis bubbled into the solution for 15 min, with re-heating at atemperature in the region of 78° C. for 70 hours. The reaction medium isconcentrated under reduced pressure (2 kPa) at a temperature in theregion of 50° C. and the residue is then basified to a pH of about 10with sodium carbonate solution. This aqueous phase is extracted with 3times 100 cm³ of dichloromethane and the combined organic phases arethen dried over sodium sulfate, filtered and evaporated under reducedpressure (2 kPa) at a temperature in the region of 40° C. to give 12.2 gof ethyl 2-amino-3-(3-nitrophenyl)propanoate in the form of anorange-colored oil. 1H NMR spectrum (250 MHz, (CD₃)₂SO-d₆, δ in ppm):1.14 (t, J=7 Hz: 3H); 1.88 (unres. mult.: 2H); 2.92 (dd, J=13 and 7 Hz:1H); 3.02 (dd, J=13 and 6 Hz: 1H); 3.62 (dd, J=7 and 6 Hz: 1H); 4.05 (q,J=7 Hz: 2H); 7.59 (resolved t, J=8.5 and 1.5 Hz: 1H); 7.71 (broad d, J=8Hz: 1H); from 8.05 to 8.20 (mt: 2H).

3-Nitrophenylalanine hydrochloride: A suspension of 34 g of diethyl2-(acetylamino)-2-(3-nitrobenzyl)malonate in 510 cm³ of concentratedhydrochloric acid is heated at a temperature in the region of 100° C.for 18 hours: a vigorous evolution of gas takes place and the suspensiondissolves when hot. The reaction mixture is then cooled to a temperaturein the region of 0° C., after which it is stirred for 1 hour at 0° C.and finally filtered through a sinter funnel. The filter cake is washedwith twice 50 cm³ of filtrate and dried in a fume cupboard and then inan oven under vacuum (10 Pa) at a temperature in the region of 60° C.23.4 g of 3-nitrophenylalanine hydrochloride are obtained in the form ofwhite crystals melting at 222° C.

Diethyl 2-(acetylamino)-2-(3-nitrobenzyl)-malonate: 3.1 g of sodium areadded, while stirring under an inert atmosphere, to 300 cm³ of ethanol.After total consumption of the sodium, 29.1 g of diethylacetamidomalonate are added and the mixture is then heated at atemperature in the region of 78° C. for 20 minutes. A solution of 23 gof 3-nitrobenzyl chloride in 100 cm³ of ethanol is then added andheating is continued at this same temperature for 18 hours. The reactionmixture is cooled to a temperature in the region of 0° C. After stirringunder these cold conditions for 1 hour, the precipitate formed isfiltered off on a sinter funnel and the filter cake is washed with twice50 cm³ of filtrate and then twice 50 cm³ of water. After drying under afume cupboard and then in an oven under vacuum (10 Pa) at a temperaturein the region of 50° C., 34 g of diethyl2-(acetylamino)-2-(3-nitrobenzyl)malonate are obtained in the form ofwhite crystals melting at 156° C.

EXAMPLE 3(+)-(4R,5S)-4-Benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine

A suspension of 1.8 g ofN-[(1R,2S)-1-benzyl-2-hydroxypropyl]-N′-tert-butylthiourea(diastereoisomer A) in 21 cm³ of 6N hydrochloric acid is heated at atemperature in the region of 100° C. for 6 hours. A further 10 cm³ of 6Nhydrochloric acid are added and heating is continued for 6 hours. Thereaction medium is filtered while hot through a sinter funnel and theinsoluble material is washed with twice 5 cm³ of hot 6N hydrochloricacid. The filtrate is cooled to a temperature in the region of 0° C.,after which 20 cm³ of water are added and this mixture is finallybasified with 30 cm³ of 30% sodium hydroxide. The resulting mixture isextracted with 3 times 50 cm³ of dichloromethane. The combined organicphases are dried over sodium sulfate, filtered and concentrated underreduced pressure (2 kPa) at a temperature in the region of 40° C. 1 g ofa pink oil is obtained, and is purified by chromatography under apressure of argon (50 kPa) on a column of silica gel (particle size40-63 μm; diameter 3 cm; height 35 cm), eluting with a mixture of 90%dichloromethane/10% methanol. The fractions containing the expectedproduct are combined and concentrated under reduced pressure (2 kPa) ata temperature in the region of 40° C. 0.31 g of(+)-(4R,5S)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine isobtained in the form of white crystals melting at 90° C. [¹H NMRspectrum (300 MHz, (CD₃)₂SO-d₆ with addition of a few drops ofCD₃COOD-d₄, δ in ppm): 1.31 (d, J=7 Hz: 3H); 2.89 (dd, J=14 and 7.5 Hz:1H); 3.01 (dd, J=14 and 7.5 Hz: 1H); 3.91 (mt: 1H); 4.41 (mt: 1H); from7.15 to 7.40 (mt: 5H). The relative stereochemistry at positions 4 and 5was validated by NOE. A strong response of the methylene of the benzylis noted after irradiating the methyl: (α_(D) ²⁰=+29.6±0.8 at aconcentration of 0.5% in methanol)].

N-[(1R,2S)-1-benzyl-2-hydroxypropyl]-N′-tert-butylthiourea: A solutionof 12.9 g of a 75%/25% mixture of the 2 diastereoisomers of(3R)-3-amino-4-phenyl-2-butanol in 160 cm³ of ethanol, to which 9.50 cm³of tert-butyl isothiocyanate have been added, is stirred at roomtemperature for 36 hours and then heated for 2 hours at a temperature inthe region of 60° C. The reaction medium is concentrated under reducedpressure (2 kPa) at a temperature in the region of 40° C. to give 20.8 gof a yellow oil. This oil is purified by chromatography under a pressureof argon (50 kPa) on a column of silica gel (particle size 40-63 μm;diameter 5 cm; height 50 cm), eluting with a mixture of 95%dichloromethane/5% ethyl acetate. The fractions containingdiastereoisomer A are evaporated under reduced pressure (2 kPa) at atemperature in the region of 40° C. 1.95 g ofN-[(1R,2S)-1-benzyl-2-hydroxypropyl]-N′-tert-butylthiourea are obtainedin the form of pale yellow crystals melting at 128° C. ¹H NMR spectrum(250 MHz, (CD₃)₂SO-d₆, δ in ppm): 0.96 (d, J=7 Hz: 3H); 1.42 (s: 9H);2.78 (limiting AB: 2H); 3.64 (mt: 1H); 4.33 (mt: 1H); 5.02 (d, J=4 Hz:1H); from 7.10 to 7.40 (mt, 6H); 7.44 (broad s, 1H). By concentratingthe fractions corresponding to diastereoisomer B under the sameconditions, 6.5 g ofN-[(1R,2R)-1-benzyl-2-hydroxypropyl]-N′-tert-butylthiourea are obtainedin the form of white crystals melting at 155° C. ¹H NMR spectrum (250MHz, (CD₃)₂SO-d₆, δ in ppm): 1.08 (d, J=7 Hz: 3H); 1.39 (s: 9H); 2.80(limiting AB: 2H); 3.68 (mt: 1H); 4.42 (unres. mult.: 1H); 4.78 (unres.mult.: 1H); 7.08 (d, J=8.5 Hz: 1H); from 7.10 to 7.40 (mt: 6H).

(3R)-3-Amino-4-phenyl-2-butanol: A solution of 19.3 g of tert-butyl(1R)-1-benzyl-2-hydroxypropylcarbamate in 160 cm³ of dioxane and 67 cm³of 6.5N hydrochloric dioxane is stirred at room temperature for 5 hoursand is then concentrated under reduced pressure (2 kPa) at a temperaturein the region of 40° C. A yellow oil is obtained, and is taken up in 50cm³ of water and basified to a pH in the region of 10 with potassiumcarbonate. This mixture is extracted with 3 times 100 cm³ of ethylacetate and the combined organic phases are then dried over sodiumsulfate, filtered and evaporated under reduced pressure (2 kPa) at atemperature in the region of 40° C. 12.9 g of a 75%/25% mixture of thetwo diastereoisomers A and B of (3R)-3-amino-4-phenyl-2-butanol areobtained in the form of an orange-colored oil. ¹H NMR spectrum (300 MHz,(CD₃)₂SO-d₆, δ in ppm). A mixture of diastereoisomers is observed: from0.70 to 1.50 (broad unres. mult.: 2H); 1.08 (d, J=6 Hz: 3H); from 2.25to 2.45 (mt: 1H); from 2.70 to 2.85 (mt: 2H); 3.44 (mt: 1H); from 4.25to 4.75 (unres. mult.: 1H); from 7.10 to 7.35 (mt: 5H).

tert-Butyl (1R)-1-benzyl-2-hydroxypropylcarbamate: A solution of 21 g oftert-butyl (1R)-1-benzyl-2-oxopropylcarbamate in 200 cm³ of ethanolunder an inert atmosphere is cooled to a temperature in the region of10° C., followed by portionwise addition of 4.55 g of sodiumborohydride. The temperature of the reaction medium is allowed to riseto room temperature with stirring, and the stirring is then continuedfor 18 hours. The reaction medium is concentrated under reduced pressure(2 kPa) at a temperature in the region of 40° C., to give white crystalswhich are taken up in 150 cm³ of water. This mixture is stirred for 2hours at room temperature and then filtered through a sinter funnel. Thefilter cake is washed with twice 150 cm³ of water. After dryingovernight in a fume cupboard, 19.37 g of tert-butyl(1R)-1-benzyl-2-hydroxypropylcarbamate are obtained in the form of whitecrystals melting at 127° C. ¹H NMR spectrum (300 MHz, (CD₃)₂SO-d₆ withaddition of a few drops of CD₃COOD-d₄, δ in ppm). A mixture of twodiastereoisomers in 70/30 proportions is observed: 1.04 and 1.10 (2d,J=6 Hz: 3H); 1.29 and 1.32 (2s: 9H); from 2.40 to 3.10 (mt: 2H); from3.35 to 3.70 (mt: 2H); 6.40 and 6.54 (2d, J=9 Hz: 1H); from 7.10 to 7.35(mt: 5H).

tert-Butyl (1R)-1-benzyl-2-oxopropylcarbamate: A mixture of 26.7 9 oftert-butyl (1R)-1-benzyl-2-[methoxy(methyl)amino]-2-oxoethylcarbamate in534 cm³ of tetrahydrofuran dried over 4 Å sieves is cooled, under aninert atmosphere, to a temperature in the region of 0° C. 87 cm³ of a 3M solution of methylmagnesium bromide in diethyl ether are then addedover 45 minutes and the resulting mixture is then stirred for 1 hour at0° C. and for 18 hours at room temperature. The reaction medium isre-cooled to a temperature in the region of 0° C., 55 cm³ of 1Nhydrochloric acid are then added dropwise and the mixture is stirred for30 minutes at this temperature. After filtration through Celite, 200 cm³of water are added to the filtrate, which is then extracted with twice200 cm³ of ethyl acetate. The combined organic phases are dried oversodium sulfate, filtered and then concentrated under reduced pressure (2kPa) at a temperature in the region of 40° C. 21.2 g of tert-butyl(1R)-1-benzyl-2-oxopropylcarbamate are obtained in the form of yellowcrystals melting at 59° C. ¹H NMR spectrum (300 MHz, (CD₃)₂SO-d₆, δ inppm): 1.34 (s: 9H); 2.13 (s: 3H); 2.71 (dd, J=14 and 10 Hz: 1H); 3.01(dd, J=14 and 5 Hz: 1H); 4.13 (mt: 1H); from 7.10 to 7.35 (mt: 6H).

tert-Butyl (1R)-1-benzyl-2-[methoxy(methyl)-amino]-2-oxoethylcarbamate:A solution of 26.5 g of D-N-Boc-phenylalanine and 22 cm³ ofN-methylmorpholine in 300 cm³ of dichloromethane is cooled, under aninert atmosphere, to a temperature in the region of −15° C. 13 cm³ ofisobutyl chloroformate are then added and the mixture is stirred for 15min at this temperature. After addition of 10.14 g ofN,O-dimethylhydroxylamine hydrochloride, stirring is continued for 1hour at a temperature in the region of −15° C. and then for 3 hours atroom temperature. 300 cm³ of water are added to the reaction medium,followed by extraction with twice 200 cm³ of dichloromethane. Thecombined organic phases are dried over sodium sulfate, filtered andconcentrated under reduced pressure (2 kPa) at a temperature in theregion of 50° C. 32.2 g of an orange-colored oil are obtained, and arepurified on a column of silica gel (particle size 40-63 μm; height 32cm), eluting with a mixture of 97% dichloromethane/3% methanol. Afterconcentration of the fractions containing the expected product underreduced pressure (2 kPa) at a temperature in the region of 40° C., 26.7g of tert-butyl(1R)-1-benzyl-2-[methoxy(methyl)amino]-2-oxoethylcarbamate are obtainedin the form of a yellow oil. ¹H NMR spectrum (250 MHz, (CD₃)₂SO-d₆, δ inppm): 1.32 (s: 9H); 2.72 (dd, J=13.5 and 10 Hz: 1H); 2.86 (dd, J=13.5and 5 Hz: 1H); 3.12 (s: 3H); 3.74 (broad s: 3H); 4.55 (mt: 1H); from7.10 to 7.35 (mt: 6H).

EXAMPLE 4(+)-(4R,5R)-4-Benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine

A suspension of 6.5 g ofN-[(1R,2R)-1-benzyl-2-hydroxypropyl]-N′-tert-butylthiourea(diastereoisomer B) in 77 cm³ of 6N hydrochloric acid is heated at atemperature in the region of 100° C. for 10 hours. The reaction mediumis then concentrated under reduced pressure (2 kPa) at a temperature inthe region of 40° C. to give a yellow oil which is taken up in 100 cm³of water. This aqueous phase is washed with twice 50 cm³ ofdichloromethane and is then basified to a pH in the region of 10 byaddition of 5 cm³ of concentrated sodium hydroxide. The resultingmixture is then extracted with 3 times 50 cm³ of dichloromethane. Thecombined organic phases are dried over sodium sulfate, filtered and thenconcentrated under reduced pressure (2 kPa) at a temperature in theregion of 40° C. 4.09 g of(+)-(4R,5R)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine areobtained in the form of white crystals melting at 89° C. [¹H NMRspectrum (300 MHz, (CD₃)₂SO-d₆, δ in ppm): 1.22 (d, J=7 Hz: 3H); 2.66(dd, J=13 and 7 Hz: 1H); 2.76 (dd, J=13 and 7 Hz: 1H); 3.54 (mt: 1H);3.95 (mt: 1H); from 5.60 to 6.45 (unres. mult.: 2H); from 7.10 to 7,40(mt: 5H). The relative stereochemistry in positions 4 and 5 wasvalidated by NOE. A strong response of the proton H4 is noted afterirradiating the methyl; (α_(D) ²⁰=+83.9±1.3 at a concentration of 0.5%in methanol)].

EXAMPLE 5 (−)-(4R)-4-(3-Thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylaminehydrochloride

A mixture of 0.94 g ofN-(tert-butyl)-N′-[(1R)-2-hydroxy-1-(3-thienylmethyl)ethyl]thiourea in9.2 cm³ of 6N hydrochloric acid is heated at a temperature in the regionof 100° C. with stirring for 3 hours and is then concentrated underreduced pressure (2 kPa) at a temperature in the region of 40° C. Agreenish oil is obtained, which is taken up in 10 cm³ of acetone to givea sticky gum. 1.5 cm³ of ethanol are then added, followed by dropwiseaddition, with stirring, of 6 cm³ of diethyl ether. The crystalsobtained are filtered off on a sinter funnel, washed with diethyl etherand then dried in an oven under vacuum (10 Pa) at a temperature in theregion of 50° C. 0.5 g of(−)-(4R)-4-(3-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylaminehydrochloride is obtained in the form of gray crystals melting at 152°C. ¹H NMR spectrum (400 MHz, (CD₃)₂SO-d₆, δ in ppm): 2.99 (mt: 2H); 3.26(dd, J=11 and 5.5 Hz: 1H); 3.59 (dd, J=11 and 8 Hz: 1H); 4.54 (mt: 1H);7.10 (dd, J=5.5 and 1 Hz: 1H); 7.38 (mt: 1H); 7.54 (dd, J=5 and 3 Hz:1H); from 9.15 to 10.55 (broad unres. mult.: 3H). (α_(D) ²⁰=−4.3±0.5 ata concentration of 0.5% in methanol).

N-(tert-butyl)-N′-[(1R)-2-hydroxy-1-(3-thienylmethyl)ethyl]thiourea: 0.9cm³ of tert-butyl isothiocyanate and then 0.82 cm³ of triethylamine areadded to a suspension of 0.9 g of (2R)-2-amino-3-(3-thienyl)-1-propanolhydrochloride in 9 cm³ of absolute ethanol stirred and under an inertatmosphere. After stirring for 66 hours at room temperature, thereaction medium is evaporated under reduced pressure (2 kPa) at atemperature in the region of 40° C. The thick brown oil obtained istaken up in 6 cm³ of water and then extracted with twice 12 cm³ of ethylacetate. The organic phase is filtered through Celite and washed withtwice 4 cm³ of saturated aqueous sodium chloride solution, dried overmagnesium sulfate and evaporated under reduced pressure (2 kPa) at atemperature in the region of 40° C. A brown oil is obtained, whichcrystallizes rapidly under cold conditions and which is dried in an ovenunder vacuum (10 Pa) at a temperature in the region of 48° C. to give0.97 g ofN-(tert-butyl)-N′-[(1R)-2-hydroxy-1-(3-thienylmethyl)ethyl]thiourea inthe form of a beige-colored solid melting at 109° C. ¹H NMR spectrum(400 MHz, (CD₃)₂SO-d₆, δ in ppm): 1.43 (s: 9H); 2.84 (mt: 2H); 3.38 (mt:2H); 4.42 (unres. mult.: 1H); 4.86 (broad t, J=4.5 Hz: 1H); 7.04 (broadd, J=5 Hz: 1H); from 7.10 to 7.20 (mt: 2H); 7.25 (broad s: 1H); 7.46(dd, J=5 and 3 Hz: 1H).

(2R)-2-Amino-3-(3-thienyl)-1-propanol hydrochloride: A solution of 1.4 gof N-[(1R)-2-hydroxy-1-(3-thienylmethyl)ethyl]acetamide in 17.6 cm³ ofaqueous 6N hydrochloric acid is heated with stirring at a temperature inthe region of 100° C. for 2 hours. The reaction mixture is thenconcentrated under reduced pressure (2 kPa) at a temperature in theregion of 40° C. to give a greenish oil, which crystallizes from 60 cm³of acetone. The crystals are filtered off on a sinter funnel, washedwith acetone and then dried in an oven under vacuum (10 Pa) at atemperature in the region of 50° C. 0.92 g of(2R)-2-amino-3-(3-thienyl)-1-propanol hydrochloride is obtained in theform of an off-white solid. ¹H NMR spectrum (400 MHz, (CD₃)₂SO-d₆, δ inppm): 2.93 (mt: 2H); from 3.25 to 3.50 (mt: 2H); 3.53 (broad d, J=11 Hz:1H); 5.37 (unres. mult.: 1H); 7.07 (broad d, J=5 Hz: 1H); 7.35 (mt: 1H);7.53 (dd, J=5 and 3 Hz: 1H); 8.18 (unres. mult.: 3H)

N-[(1R)-2-Hydroxy-1-(3-thienylmethyl)-ethyl]acetamide: A solution of2.15 g of ethyl (2R)-2-(acetylamino)-3-(3-thienyl)propanoate in 24 cm³of ethanol, stirred under an inert atmosphere, is brought to atemperature of 20° C. 0.5 g of sodium borohydride is added and thereaction medium, which is slightly brown, is stirred for 24 hours atroom temperature. A further 0.2 g of sodium borohydride is added andstirring is continued for 24 hours. After evaporation of the reactionmixture under reduced pressure (2 kPa) at a temperature in the region of40° C., a solid residue is obtained, which is taken up in 30 cm³ ofwater. This mixture is extracted with twice 100 cm³ of ethyl acetate andthe organic phase is then dried over magnesium sulfate and evaporatedunder reduced pressure (2 kPa) at a temperature in the region of 40° C.to give an off-white solid which is dried in an oven under vacuum (10Pa) at a temperature in the region of 48° C. 1.4 g ofN-[(1R)-2-hydroxy-1-(3-thienylmethyl)ethyl]acetamide are obtained in theform of an off-white solid melting at about 105° C. to become pasty. ¹HNMR spectrum (400 MHz, (CD₃)₂SO-d₆, δ in ppm): 1.78 (s: 3H); 2.64 (dd,J=14 and 8 Hz: 1H); 2.87 (dd, J=14 and 5.5 Hz: 1H); from 3.20 to 3.40(mt: 2H); 3.90 (mt: 1H); 4.76 (t, J=5.5 Hz: 1H); 6.99 (dd, J=5 and 1 Hz:1H); 7.16 (dd, J=3 and 1 Hz: 1H); 7.43 (dd, J=5 and 3 Hz: 1H); 7.70 (d,J=8.5 Hz: 1H).

Ethyl (2R)-2-(acetylamino)-3-(3-thienyl)propanoate: 3.95 g of ammoniumhydrogen carbonate and 35 cm³ of deionized water are added to a stirredsolution, under an inert atmosphere, of 2.41 g of ethyl2-(acetylamino)-3-(3-thienyl)propanoate in 17 cm³ of acetonitrile. 0.017g of type-II α-chymotrypsin is added and the pH of the reaction mediumis then in the region of 8. This mixture is stirred for 1 hour at roomtemperature and, after checking that the pH is still at 8, a further0.017 g of type-II α-chymotrypsin is added. After stirring for 1 hour,with the pH remaining constant, a further 0.017 g of type-IIα-chymotrypsin is introduced and stirring of the reaction mixture iscontinued for 19 hours at room temperature. The acetonitrile isevaporated off under reduced pressure (2 kPa) at a temperature in theregion of 33° C. and 25 cm³ of ethyl acetate are then added to theresidual aqueous phase. The emulsion obtained is filtered through Celiteand the aqueous phase is then extracted with twice 25 cm³ of ethylacetate. The organic phases are combined, washed with twice 15 cm³ ofsodium carbonate solution and then evaporated under reduced pressure (2kPa) at a temperature in the region of 40° C. The solid residue is thendried in an oven under vacuum (10 Pa) at room temperature. 1.1 g ofethyl (2R)-2-(acetylamino)-3-(3-thienyl)propanoate are obtained in theform of a beige-colored solid melting at about 75° C.

Ethyl 2-(acetylamino)-3-(3-thienyl)-propanoate: 9.83 g of lithium iodideare added in a single portion to a stirred pale yellow solution, underan inert atmosphere, of 7.7 g of diethyl2-(acetylamino)-2-(3-thienylmethyl)malonate in 62 cm³ ofdimethylformamide, and the resulting mixture is heated in an oil bath ata temperature in the region of 128° C. for 19 hours. 6.6 g of lithiumiodide are added and heating is continued for 5 hours. The reactionmedium is then evaporated under reduced pressure (2.4 kPa) at atemperature in the region of 55° C. The residual brown oil is taken upin 180 cm³ of water and is extracted with 4 times 60 cm³ of ethylacetate. The organic phases are combined, washed with 30 cm³ ofsaturated aqueous sodium chloride solution, dried over magnesium sulfateand then evaporated under reduced pressure (2 kPa) at a temperature inthe region of 62° C., to give 5.34 g of a brown oil which crystallizesunder cold conditions. The crystals are taken up in 40 cm³ of petroleumether, ground in a mortar and then filtered off on a sinter funnel anddried in an oven under vacuum (10 Pa) at room temperature. 4.9 g ofethyl 2-(acetylamino)-3-(3-thienyl)propanoate are obtained in the formof an off-white solid melting at about 60° C. ¹H NMR spectrum (400 MHz,(CD₃)₂SO-d₆, δ in ppm) 1.14 (t, J=7 Hz: 3H); 1.84 (s: 3H); 2.93 (dd,J=14 and 9 Hz: 1H); 3.03 (dd, J=14 and 5.5 Hz: 1H); 4.06 (mt: 2H); 4.44(mt: 1H); 7.02 (dd, J=5 and 1 Hz: 1H); 7.24 (mt: 1H); 7.45 (dd, J=5 and3 Hz: 1H); 8.31 (d, J=8 Hz: 1H).

Diethyl 2-(acetylamino)-2-(3-thienylmethyl)malonate: 1.54 g of sodiumare added, with stirring under an inert atmosphere, to 115 cm³ ofabsolute ethanol. After total consumption of the sodium, 14.55 g ofdiethyl acetamidomalonate are added, followed by heating at atemperature in the region of 78° C. for 20 minutes. A solution of 16.5 gof freshly prepared 3-(bromomethyl)thiophene in 50 cm³ of ethanol isthen added and heating is continued at this same temperature for 19hours. The reaction medium, which contains an insoluble white material,is cooled to a temperature in the region of 0° C. and is then filteredthrough a sinter funnel. The filtrate is concentrated under reducedpressure (2 kPa) at a temperature in the region of 40° C. and is thenfiltered through a sinter funnel. The crystals are taken up in 100 cm³of water, filtered again, washed with petroleum ether and dried in afume cupboard at room temperature. 1.45 g of diethyl2-(acetylamino)-2-(3-thienylmethyl)malonate are obtained in the form ofa white solid melting at about 92° C. After evaporation of thefiltration solvent in ambient air, the residue is taken up in 150 cm³ ofwater and is then filtered on a sinter funnel. The yellowish solidobtained is washed with 50 cm³ of water and is then dissolved in 25 cm³of absolute ethanol, followed by crystallization by addition of 25 cm³of water. After filtration, washing with 3 times 30 cm³ of petroleumether and then drying in a fume cupboard at room temperature, 6.57 g ofdiethyl 2-(acetylamino)-2-(3-thienylmethyl)malonate are obtained in theform of a white solid melting at about 92° C. ¹H NMR spectrum (300 MHz,(CD₃)₂SO-d₆, δ in ppm): 1.18 (t, J=7 Hz: 6H); 1.98 (s: 3H); 3.50 (s:2H); 4.16 (q, J=7 Hz: 4H); 6.80 (broad d, J=5 Hz: 1H); 7.14 (broad s:1H); 7.46 (dd, J=5 and 3 Hz: 1H); 8.20 (broad s: 1H).

3-(Bromomethyl)thiophene can be prepared according to J. Gourier and P.Cannone; Bull. Soc. Chim. Fr. 1971, 3299-3306.

EXAMPLE 6[3-(2-Amino-4,5-dihydrothiazol-4-yl)phenyl]-(1-iminoethyl)amine

0.15 g of benzyl ethanimidothioate hydrochloride and then 5 cm³ ofethanol are added, under an inert atmosphere and at a temperature in theregion of 0° C., to a stirred solution of 0.14 g of4-(3-aminophenyl)-4,5-dihydro-1,3-thiazol-2-ylamine in 15 cm³ ofethanol. The mixture is stirred for 1 hour at about 0° C. and then for 2hours at a temperature in the region of 20° C. A further 0.030 g ofbenzyl ethanimidothioate is added to complete the reaction, after whichthe mixture is maintained at a temperature in the region of 45° C. for24 hours. The reaction medium is evaporated under reduced pressure (5kPa) at a temperature in the region of 40° C. The residue obtained istaken up in 30 cm³ of water and the solution is washed with 30 cm³ ofdichloromethane. The aqueous solution is concentrated under the aboveconditions and the solid obtained is then triturated from diethyl ether,filtered, air-dried and purified by chromatography at atmosphericpressure on a column of silica gel (particle size 40-63μ; mass 63 g),eluting with a dichloromethane/methanol/aqueous ammonia mixture(12/3/0.5 by volume). The fractions containing the expected product arecollected. These fractions are combined and then evaporated underreduced pressure (5 kPa) at a temperature in the region of 40° C. 0.100g of [3-(2-amino-4,5-dihydrothiazol-4-yl)phenyl]-(1-iminoethyl)amine isobtained in the form of a white solid melting at 180° C. ¹H NMR spectrum(250 MHz, (CD₃)₂SO-d₆, with addition of a few drops of CD₃COOD-d₄, δ inppm): 2.28 (unres. mult.: 3H); 3.18 (dd, J=12.5 and 8.5 Hz: 1H); 3.80(dd, J=12.5 and 8.5 Hz: 1H); 5.30 (t, J=8.5 Hz: 1H); 7.21 (broad d,J=8.5 Hz: 1H); 7.27 (broad s: 1H); 7.36 (broad d, J=8.5 Hz: 1H); 7.49(broad t, J=8.5: Hz: 1H).

Benzyl ethanimidothioate hydrochloride can be obtained by applying themethod described in patent WO 96/19440.

4-(3-Aminophenyl)-4,5-dihydro-1,3-thiazol-2-ylamine: 3 g of zinc powderare added, with stirring at a temperature in the region of 20° C., to asuspension of 2.4 g of4-(3-nitrophenyl)-4,5-dihydro-1,3-thiazol-2-ylamine hydrochloride in 50cm³ of 85% by volume of acetic acid. After stirring for 20 minutes atroom temperature, the reaction medium is filtered; the filter cake iswashed with 10 cm³ of water and the filtrate is then concentrated underreduced pressure (5 kPa) at a temperature in the region of 50° C. Theresidue obtained is taken up in methanol and then in diethyl ether, andconcentrated under the same conditions as above. This operation isrepeated a second time. The product obtained is taken up in 100 cm³ ofacetonitrile and filtered. The filtrate is concentrated as above andtaken up in 60 cm³ of water. The insoluble material is filtered off,while the filtrate is made alkaline by addition of 7 cm³ of aqueous 1Nsodium hydroxide solution. The insoluble material is separated out byfiltration and the filtrate is again concentrated as above, and taken upin 40 cm³ of a dichloromethane/methanol/aqueous ammonia mixture(40/5/0.5 by volume). The insoluble material is filtered off and thefiltrate is concentrated as above. 4.2 g of a yellow oil are obtained,and are purified by chromatography at atmospheric pressure on a columnof silica gel (particle size 40-63μ; 100 g of silica), eluting with adichloromethane/methanol/aqueous ammonia mixture (40/5/0.5 by volume).The fractions containing the product are combined and then concentrated(5 kPa) at a temperature in the region of 40° C. 0.73 g of4-(3-aminophenyl)-4,5-dihydro-1,3-thiazol-2-ylamine is obtained in theform of a yellow solid melting at 152° C.

4-(3-Nitrophenyl)-4,5-dihydro-1,3-thiazol-2-ylamine hydrochloride: Theprocess is performed as in Example 2, starting with 4.77 g ofN-(tert-butyl)-N′-[2-hydroxy-1-(3-nitrophenyl)ethyl]thiourea and 44 cm³of aqueous 6N hydrochloric acid, and this mixture is maintained at atemperature in the region of 100° C. for 2 h 30 min. After an identicalwork-up, 3.1 g of 4-(3-nitrophenyl)-4,5-dihydro-1,3-thiazol-2-ylaminehydrochloride are obtained in the form of a cream-colored solid meltingat 232° C.

N-(tert-Butyl)-N′-[2-hydroxy-1-(3-nitrophenyl)ethyl]thiourea: Theprocess is performed as in Example 2, starting with 5.1 g of2-amino-2-(3-nitrophenyl)-1-ethanol in 170 cm³ of ethanol containing 85cm³ of dichloromethane and 4.6 cm³ of tert-butyl isothiocyanate, at atemperature in the region of 20° C. for 3 days and then at a temperaturein the region of 60° C. for 7 hours. After addition of a further 0.35cm³ of tert-butyl isothiocyanate and 16 hours at a temperature in theregion of 60° C., an identical work-up gives 5.7 g ofN-(tert-butyl)-N′-[2-hydroxy-1-(3-nitrophenyl)ethyl]thiourea in the formof an ocher-colored solid melting at 162° C.

2-Amino-2-(3-nitrophenyl)-1-ethanol: The process is performed as inExample 2, starting with 1 g of ethyl 3-nitrophenylglycinate in 20 cm³of ethanol with 0.255 g of sodium borohydride and 20 hours at atemperature in the region of 20° C. After an identical work-up, 0.200 gof 2-amino-2-(3-nitrophenyl)-1-ethanol is obtained in the form of anocher-yellow paste. (R_(f)=0.18 in a 90/10 by volume mixture ofdichloromethane/methanol, on a Merck 60F₂₅₄ _(^(R)) silica plate).

Ethyl 3-nitrophenylglycinate: 2 g of 3-nitrophenylglycine are heated for20 hours with stirring at a temperature in the region of 100° C. in 100cm³ of absolute ethanol containing 20 cm³ of 6.5N hydrochloric ethanol.The suspension is filtered at a temperature in the region of 50° C.; thefiltrate is concentrated under reduced pressure (5 kPa) at a temperaturein the region of 40° C. The residue obtained is taken up in water andthen extracted with about 100 cm³ of ethyl acetate. The aqueous phase ismade alkaline by addition of sodium carbonate until a pH in the regionof 10 is obtained. The medium is extracted with ethyl acetate; thecombined extracts are washed with aqueous sodium chloride solution,dried over magnesium sulfate and then concentrated under reducedpressure (5 kPa) at 40° C. 1 g of ethyl 3-nitrophenylglycinate isobtained in the form of a yellow oil. (R_(f)=0.38 in a 95/5 by volumemixture of dichloromethane/methanol, on a Merck 60F₂₅₄ _(^(R)) silicaplate).

3-Nitrophenylglycine: 1.01 g of potassium nitrate are added slowly, at atemperature in the region of 0° C. with stirring, to a mixture of 1.51 gof D-(−)-α-phenylglycine in 6 cm³ of 95% sulfuric acid and thetemperature is then allowed to return to about 20° C. The solutionobtained is poured into 30 cm³ of ice-cold water and then brought to pH7 by addition of 18.5 cm³ of 10N sodium hydroxide, at a temperaturebelow 5° C. The mixture is stirred for 2 hours and then filtered. Thefilter cake obtained is washed with twice 50 cm³ of water and thendried. 0.60 g of 3-nitrophenyl-glycine is obtained in the form of acream-colored solid melting at 230° C.

EXAMPLE 7 (+)-(4R)-4-Benzyl-4,5-dihydro-1,3-thiazol-2-ylaminehydrochloride

The process is performed as in Example 2, starting with 2 g ofN-(tert-butyl)-N′-[(1R)-2-hydroxy-1-(phenylmethyl)ethyl]thiourea and 20cm³ of aqueous 6N hydrochloric acid. The reaction lasts 1 h 30 min.After cooling the reaction mass to a temperature in the region of 0° C.,the solution is concentrated under reduced pressure (5 kPa) at atemperature in the region of 40° C. Crystallization of the oil obtainedis initiated by addition of diethyl ether. The resulting precipitate isspin-filtered, washed with twice 10 cm³ of diethyl ether and then driedunder reduced pressure (10 Pa) at a temperature in the region of 60° C.The product is purified by taking it up in 100 cm³ of dichloromethanewith stirring for 30 minutes. After filtration of the suspension, thefilter cake is washed with twice 10 cm³ of dichloromethane and is thendried under the same conditions as above. 1.1 g of(+)-(4R)-4-phenylmethyl-4,5-dihydro-1,3-thiazol-2-ylamine hydrochlorideare obtained in the form of a white solid melting at 168° C. (α_(D)²⁰=+8.7±0.3 at a concentration of 1% in methanol).

N-(tert-Butyl)-N′-[(1R)-2-hydroxy-1-(benzyl)ethyl]thiourea: The processis performed as in Example 2, starting with 5 g of(R)-(+)2-amino-3-phenyl-1-propanol in 50 cm³ of ethanol and 5.7 g oftert-butyl isothiocyanate at a temperature in the region of 20° C. for16 hours. After an identical work-up, 8.7 g ofN-(tert-butyl)-N′-[(1R)-2-hydroxy-1-(phenylmethyl)ethyl]thiourea areobtained in the form of a white solid melting at 107° C.

EXAMPLE 8 (+)-(4R)-4-(3-Carboxybenzyl)-4,5-dihydro-1,3-thiazol-2-ylaminehydrochloride

The process is performed as in Example 2, starting with 2.31 g ofN-(tert-butyl)-N′-[(1R)-2-hydroxy-1-(3-carboxybenzyl)ethyl]thiourea in25 cm³ of 6N hydrochloric acid for 18 hours. After concentration of thereaction mixture under reduced pressure (5 kPa) at a temperature in theregion of 55° C., the residue is taken up in 20 cm³ of acetone and isthen concentrated again under the above conditions. The residue obtainedis purified by chromatography under a pressure of 50 kPa of argon, on acolumn of silica gel (particle size 40-63μ; mass of silica: 100 g),eluting with a chloroform/methanol/20% aqueous ammonia mixture (12/6/1by volume) and collecting 30 cm³ fractions. Fractions 16 to 38 arecombined and then concentrated under reduced pressure (5 kPa) at atemperature in the region of 40° C. The solid obtained is dissolved in10 cm³ of aqueous 6N hydrochloric acid and is then concentrated aspreviously. After taking up the residue obtained in 10 cm³ of acetone,the resulting insoluble material is filtered off; the filtrate isconcentrated as above. A solid is obtained, which is dried for 5 hoursin an oven at 40° C., under reduced pressure (8 Pa). 0.650 g of(+)-(4R)-4-(3-carboxybenzyl)-4,5-dihydro-1,3-thiazol-2-ylaminehydrochloride is obtained in the form of a beige-colored solid meltingat 151° C. (α_(D) ²⁰=+13.4±0.6 at a concentration of 0.5% in methanol).

N-(tert-Butyl)-N′-[(1R)-2-hydroxy-1-(3-carboxybenzyl)ethyl]thiourea: Theprocess is performed as in Example 2, starting with 1.82 g of(2R)-2-amino-3-(3-carboxyphenyl)-1-propanol hydrochloride in 20 cm³ ofethanol, 4.2 cm³ of triethylamine and 1.7 cm³ of tert-butylisothiocyanate. After heating for 21 hours at a temperature in theregion of 60° C. and an identical work-up, 2.31 g ofN-(tert-butyl)-N′-[(1R)-2-hydroxy-1-(3-carboxybenzyl)ethyl]thiourea areobtained in the form of a light brown foam. (R_(f)=0.33 in a 12/6/1 byvolume mixture of chloroform/methanol/aqueous ammonia, on a Merck 60F₂₅₄_(^(R)) silica plate).

(2R)-2-Amino-3-(3-carboxyphenyl)-1-propanol hydrochloride: The processis performed as in Example 2, starting with 1.96 g ofN-[(1R)-2-hydroxy-1-(3-carboxybenzyl)ethyl]acetamide in 14 cm³ ofaqueous 6N hydrochloric acid heated at a temperature in the region of100° C. for 17 hours. After an identical work-up, 2.16 g of(2R)-2-amino-3-(3-carboxyphenyl)-1-propanol hydrochloride are obtainedin the form of a white solid melting at 194° C.

N-[(1R)-2-Hydroxy-1-(3-cyanobenzyl)ethyl]-acetamide: The process isperformed as in Example 2, starting with 3.3 g of ethyl(2R)-2-acetylamino-3-(3-cyanophenyl)propanoate and 1.23 g of sodiumborohydride in 50 cm³ of ethanol and working at a temperature in theregion of −30° C. After stirring for 16 hours at a temperature in theregion of 20° C., the reaction medium is evaporated under reducedpressure (5 kPa) at a temperature in the region of 45° C. and theresidue obtained is then stirred in a mixture of 100 cm³ of water and100 cm³ of ethyl acetate. The organic phase is separated out aftersettling has taken place and the aqueous phase is extracted with twice100 cm³ of ethyl acetate. The organic extracts are combined and thenwashed with twice 50 cm³ of water, dried over magnesium sulfate,filtered and evaporated under reduced pressure (5 kPa) at a temperaturein the region of 45° C. 2.13 g ofN-[(1R)-2-hydroxy-1-(3-cyanobenzyl)ethyl]acetamide are obtained in theform of a white solid. (α_(D) ²⁰=+7.5±0.6 at a concentration of 0.5% inmethanol).

Ethyl (2R)-2-acetylamino-3-(3-cyanophenyl)-propanoate: The process isperformed as in Example 2, starting with 11.39 g of ethyl(2RS)-2-acetylamino-3-(3-cyanophenyl)propanoate, 17.39 g of ammoniumhydrogen carbonate and 0.1 g of α-chymotrypsin in 200 cm³ of water and70 cm³ of acetonitrile. After stirring for 24 hours at a temperature inthe region of 20° C. and an identical work-up, 5.40 g of ethyl(2R)-2-acetylamino-3-(3-cyanophenyl)propanoate are obtained in the formof a beige-colored solid. (R_(f)=0.76 in a 40/10/20 by volume mixture ofn-butanol/acetic acid/water, on a Merck 60F₂₅₄ _(^(R)) silica plate).

Ethyl (2RS)-2-acetylamino-3-(3-cyanophenyl)-propanoate: The process isperformed as in Example 5, starting with 14.9 g of ethyl2-acetylamino-2-(3-cyanobenzyl)malonate, 30 g of anhydrous lithiumiodide and 150 cm³ of dry dimethylformamide. After stirring for 5 hoursat a temperature in the region of 150° C., the reaction mass is cooledto room temperature. 1500 cm³ of water are added and the mixture isextracted with 3 times 300 cm of ethyl acetate. The extracts arecombined, dried over magnesium sulfate, filtered and concentrated underreduced pressure (5 kPa) at a temperature in the region of 45° C. Afterdrying in an oven at a temperature in the region of 40° C. under reducedpressure (10 Pa), 11.39 g of ethyl(2RS)-2-acetylamino-3-(3-cyanophenyl)propanoate are obtained in the formof a beige-colored paste. (R_(f)=0.51 in a 90/10 by volume mixture ofethyl acetate/cyclohexane, on a Merck 60F₂₅₄ _(^(R)) silica plate).

Ethyl 2-acetylamino-2-(3-cyanobenzyl)-malonate: The process is performedas in Example 5, starting with 27.7 g of diethyl acetamidomalonate, 25 gof 3-cyanobenzyl bromide and 3.2 g of sodium in 400 cm³ of absoluteethanol. After an identical work-up, the cooled reaction mass isfiltered and the filter cake is washed with twice 50 cm³ of ethanol andthen with twice 50 cm³ of water. After drying in an oven under reducedpressure (10 Pa) at a temperature in the region of 40° C., 21.98 g of awhite powder are obtained. The filtrate is evaporated under reducedpressure (5 kPa) at a temperature in the region of 50° C.; a foam isobtained, which is taken up in 100 cm³ of water and extracted with 100cm³ of ethyl acetate and then twice 50 cm³ of the same solvent. Theextracts are combined, washed with twice 50 cm³ of water, dried overmagnesium sulfate, filtered and evaporated under reduced pressure (5kPa) at a temperature in the region of 45° C. The residue obtained istaken up in 20 cm³ of ethanol. The crystals obtained are spin-filtered,washed with ethanol and dried in an oven under reduced pressure (10 Pa)at a temperature in the region of 40° C. The two crops are combined togive 31.94 g of ethyl 2-acetylamino-2-(3-cyanobenzyl)-malonate in theform of a white powder melting at 138° C.

EXAMPLE 9 (+)-(4R)-4-(4-Aminobutyl)-4,5-dihydro-1,3-thiazol-2-ylaminedihydrochloride

The process is performed as in Example 1, starting with 5.9 g of benzyl(5R)-5-{[(tert-butylamino)carbothioyl]amino}-6-hydroxyhexylcarbamate in40 cm³ of aqueous 6N hydrochloric acid at a temperature in the region of100° C. for 3 hours. After concentration of the reaction medium underreduced pressure (5 kPa) at a temperature in the region of 50° C., theresidue obtained is taken up in ethanol and then concentrated againunder the above conditions. The paste obtained is crystallized bytrituration from an ethanol/methanol mixture (8/2 by volume). Thecrystals are filtered off, washed with acetonitrile and air-dried. 1.3 gof (+)-(4R)-4-(4-aminobutyl)-4,5-dihydro-1,3-thiazol-2-ylaminedihydrochloride are obtained in the form of a white solid melting at188° C. (α_(D) ²⁰=+16.2±0.7 at a concentration of 0.5% in methanol).

Benzyl(5R)-5-{[(tert-butylamino)-carbothioyl]amino}-6-hydroxyhexylcarbamate:1.78 g of lithium chloride and then 1.6 g of sodium borohydride areadded, under an inert atmosphere, to a stirred solution of 12.7 g ofethyl(2R)-6-{[(benzyloxy)-carbonyl]amino}-2-{[(tert-butylamino)carbothioyl]-amino}hexanoatein 130 cm³ of ethanol and 65 cm³ of tetrahydrofuran, cooled to between0° C. and 5° C. After stirring for 16 hours at a temperature in theregion of 20° C., a further 0.4 g of borohydride is added and themixture is maintained at about 80° C. for 4 hours. The reaction mediumis filtered and the filter cake is washed with ethanol. The filtrate isconcentrated under reduced pressure (5 kPa) at a temperature in theregion of 40° C. and the residue obtained is taken up in adichloromethane/ethyl acetate mixture (85/15 by volume) and left undercold conditions at about 5° C. The crystalline product is spin-filteredand purified by chromatography at atmospheric pressure on a column ofsilica gel (particle size 40-63μ; mass of silica: 600 g), eluting with adichloromethane/ethyl acetate mixture (85/15 by volume). The fractionscontaining the expected product are collected. These fractions arecombined and then concentrated under reduced pressure (5 kPa) at atemperature in the region of 40° C. 6.9 g of benzyl(5R)-5-{[(tert-butylamino)carbothioyl]amino}-6-hydroxyhexylcarbamate areobtained in the form of a colorless oil. (α_(D) ²⁰=+24.0±0.8 at aconcentration of 0.5% in methanol).

Ethyl(2R)-6-{[(benzyloxy)carbonyl]amino}-2-{[(tert-butylamino)carbothioyl]amino}hexanoate:The process is performed as in Example 2, starting with 7.4 g of ethyl(2R)-2-amino-6-{[(benzyloxy)carbonyl]-amino}hexanoate with 5 cm³ oftert-butyl isothiocyanate in 200 cm³ of anhydrous ethanol at atemperature in the region of 20° C. for 20 hours. The reaction iscompleted by addition of a further 1 cm³ of isothiocyanate and heatingfor 2 hours at a temperature in the region of 80° C. The reaction mediumis concentrated under reduced pressure (5 kPa) at a temperature in theregion of 40° C. The residue obtained is taken up in ether andconcentrated again under the above conditions. 13 g of ethyl(2R)-6-{[(benzyloxy)carbonyl]amino}-2-{[(tert-butylamino)carbothioyl]amino}hexanoateare obtained in the form of a colorless oil. (α_(D) ²⁰=−12.5±0.5 at aconcentration of 0.5% in methanol).

Ethyl (2R)-2-amino-6-{[(benzyloxy)carbonyl]-amino}hexanoate: 3.9 cm³ ofthionyl chloride are added to a stirred suspension of 7.9 g of(2R)-2-amino-6-{[(benzyloxy)carbonyl]amino}hexanoic acid(Nε-CBZ-D-lysine) in 120 cm³ of anhydrous ethanol cooled to atemperature in the region of −25° C. The mixture is stirred for 3 hoursat this temperature and is then allowed to warm to about 20° C. Afterleaving for 3 days, the reaction mass is concentrated under reducedpressure (5 kPa) at a temperature in the region of 40° C. The residueobtained is taken up in 200 cm³ of ethyl acetate and the resultingsolution is washed with aqueous sodium carbonate solution and then withaqueous sodium chloride solution. The organic solution is dried overmagnesium sulfate, filtered and concentrated under reduced pressure (5kPa) at a temperature in the region of 40° C. 7.4 g of ethyl(2R)-2-amino-6-{[(benzyloxy)-carbonyl]amino}hexanoate are obtained inthe form of a pale yellow oil. (α_(D) ²⁰=−11.7±0.6 at a concentration of0.5% in methanol).

EXAMPLE 10 (−)-(4S)-4-(3-Nitrobenzyl)-4,5-dihydro-1,3-thiazol-2-ylaminehydrochloride

The process is performed as in Example 2, starting withN-(tert-butyl)-N′-[(1S)-2-hydroxy-1-(3-nitrobenzyl)ethyl]thiourea in 80cm³ of aqueous 6N hydrochloric acid. The heating time is 7 hours. Theproduct is isolated in an identical manner and then purified bychromatography under an argon pressure of 80 kPa, on a column of silicagel (particle size 40-63μ; diameter 3.5 cm; height 30 cm), eluting witha dichloromethane/methanol mixture (95/5 by volume). The fractionscorresponding to the expected product are collected. These fractions arecombined and then concentrated under reduced pressure (5 kPa) at atemperature in the region of 40° C. 3.90 g of(−)-(4S)-4-(3-nitrobenzyl)-4,5-dihydro-1,3-thiazol-2-ylaminehydrochloride are obtained in the form of a white solid melting at 220°C. (α_(D) ²⁰=−18.4±0.05 at a concentration of 0.5% in methanol).

N-(tert-Butyl)-N′-[(1S)-2-hydroxy-1-(3-nitrobenzyl)ethyl]thiourea: Theprocess is performed as in Example 2, starting with 5.65 g of(2S)-2-amino-3-(3-nitrophenyl)-1-propanol hydrochloride, 3.7 cm³ oftert-butyl isothiocyanate and 3.41 cm³ of triethylamine in 60 cm³ ofethanol. After stirring for 3 days at a temperature in the region of 20°C. and then heating for 30 minutes at a temperature in the region of 60°C., 3.7 cm³ of tert-butyl isothiocyanate are added to the reactionmedium and heating is then continued for a further 3 hours at the sametemperature. After an identical work-up, 6.45 g ofN-(tert-butyl)-N′-[(1S)-2-hydroxy-1-(3-nitrobenzyl)ethyl]thiourea areobtained in the form of a yellow foam. (R_(f)=0.61 in a 40/5/0.5 byvolume mixture of dichloromethane/methanol/aqueous ammonia, on a Merck60F₂₅₄ _(^(R)) silica plate).

(2S)-2-Amino-3-(3-nitrophenyl)-1-propanol hydrochloride: The process isperformed as in Example 2, starting with 5.8 g ofN-[(1S)-2-hydroxy-1-(3-nitrobenzyl)ethyl]acetamide in 60 cm³ of aqueous6N hydrochloric acid, for 10 hours at a temperature in the region of100° C. After cooling the medium, the precipitate is filtered off andthen washed with 30 cm³ of acetone and 3 times 50 cm³ of ether, anddried in an oven under reduced pressure (10 Pa) at a temperature in theregion of 60° C. The filtrate is concentrated under reduced pressure (5kPa) at about 50° C. The residue obtained is taken up in 30 cm³ ofdiethyl ether and the crystals are filtered off, washed with twice 30cm³ of ether and dried in an oven under the same conditions as above.The 2 crops crystallized are combined. 5.65 g of(2S)-2-amino-3-(3-nitrophenyl)-1-propanol hydrochloride are obtained inthe form of a beige-colored solid melting at 188° C.

N-[(1S)-2-Hydroxy-1-(3-nitrobenzyl)ethyl]-acetamide: The process isperformed as in Example 2, starting with 7.15 g of ethyl(2S)-2-(acetylamino)-3-(3-nitrophenyl)propanoate and 1.46 g of sodiumborohydride in 70 cm³ of ethanol. After an identical work-up, 5.8 g ofN-[(1S)-2-hydroxy-1-(3-nitrobenzyl)-ethyl]acetamide are obtained in theform of a white solid melting at 131° C.

Ethyl (2S)-2-(acetylamino)-3-(3-nitrophenyl)-propanoate can be preparedaccording to Rivier et al., J. Med. Chem. (1995), 2658.

EXAMPLE 11(−)-(4S,5S)-4-Benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine

The process is performed as in Example 3, starting with 3.9 g ofdiastereoisomer A of theN-(tert-butyl)-N′-((1S)-1-benzyl-2-hydroxypropyl)thiourea in 46 cm³ ofaqueous 6N hydrochloric acid. After heating for 5 hours at a temperaturein the region of 100° C., the reaction mass is concentrated underreduced pressure (5 kPa) at a temperature in the region of 50° C. Theoil obtained is dissolved in 50 cm³ of water; the solution is washedwith twice 50 cm³ of dichloromethane. The aqueous phase is made alkalineby addition of 3 cm³ of 30% caustic soda and then extracted with 3 times50 cm³ of dichloromethane. The organic extracts are combined and driedover sodium sulfate. After filtration and concentration under reducedpressure (5 kPa) at a temperature in the region of 40° C., 2.5 g of(−)-(4S,5S)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine areobtained in the form of a white solid melting at 89° C. (trans isomer).(α_(D) ²⁰=−87.3±1.3 at a concentration of 0.5% in methanol).

N-(tert-Butyl)-N′-((1S)-1-benzyl-2-hydroxypropyl)thiourea: The processis performed as in Example 3, starting with 9.5 g of(3S)-3-amino-4-phenyl-2-butanol in 80 cm³ of ethanol and in the presenceof 7.86 cm³ of tert-butyl isothiocyanate. After stirring the mixture for3 days at a temperature in the region of 20° C. and an identicalwork-up, 15.9 g of an oil are obtained, and are purified bychromatography under a pressure of argon (50 kPa), on a column of silicagel (particle size 40-63μ; diameter 5 cm; height of silica 38 cm),eluting with a dichloromethane/ethyl acetate mixture (95/5 by volume).The fractions containing diastereoisomer A are combined and evaporatedunder reduced pressure (5 kPa) at a temperature in the region of 40° C.3.98 g of diastereoisomer A ofN-(tert-butyl)-N′-((1S)-1-benzyl-2-hydroxypropyl)thiourea are obtainedin the form of a white solid melting at 156° C. By concentrating thefractions corresponding to diastereoisomer B under the same conditions,0.72 g of diastereoisomer B ofN-(tert-butyl)-N′-((1S)-1-benzyl-2-hydroxypropyl)thiourea is obtained inthe form of a yellow solid melting at 116° C.

(3S)-3-Amino-4-phenyl-2-butanol: The process is performed as in Example3, starting with 17.6 g of tert-butyl(1S)-1-benzyl-2-hydroxypropylcarbamate in 145 cm³ of dioxane and 61 cm³of 6.5N hydrochloric dioxane, stirring for 16 hours at a temperature inthe region of 20° C. After an identical work-up, 9.56 g of(3S)-3-amino-4-phenyl-2-butanol are obtained in the form of anorange-colored oil as a mixture of the two diastereoisomers (80/20).(R_(f)=0.25 in a 40/5/0.5 by volume mixture ofdichloromethane/methanol/aqueous ammonia, on a Merck 60F₂₅₄ _(^(R))silica plate).

tert-Butyl (1S)-1-benzyl-2-hydroxypropyl-carbamate: The process isperformed as in Example 3, starting with 2.66 g of tert-butyl(1S)-1-benzyl-2-oxopropylcarbamate in 25 cm³ of ethanol, with 0.58 g ofsodium borohydride. After 4 h 30 min at a temperature in the region of20° C., the reaction mixture is worked up in an identical manner. 2.7 gof tert-butyl (1S)-1-benzyl-2-hydroxypropylcarbamate are obtained in theform of a white solid melting at 125° C., as a mixture of the twodiastereoisomers (70/30).

tert-Butyl (1S)-1-benzyl-2-oxopropyl-carbamate: The process is performedas in Example 3, starting with 5 g of tert-butyl(1S)-1-benzyl-2-[methoxy(methyl)amino]-2-oxoethylcarbamate, 16 cm³ of a1M solution of methylmagnesium bromide in ether, and 100 cm³ ofanhydrous tetrahydrofuran. Once the reaction is complete, the reactionmedium is stirred for 18 hours at a temperature in the region of 20° C.After an identical work-up, 3.91 g of an orange-colored oil areobtained, and are purified by chromatography at atmospheric pressure ona column of silica gel (particle size 63-200μ; diameter 3.5 cm; height20 cm), eluting with dichloromethane. The fractions corresponding to theexpected product are collected. These fractions are combined and thenconcentrated under reduced pressure (5 kPa) at a temperature in theregion of 40° C. 2.82 g of tert-butyl (1S)-1-benzyl-2-oxopropylcarbamateare obtained in the form of a white solid melting at 62° C.

tert-Butyl (1S)-1-benzyl-2-[methoxy(methyl)-amino]-2-oxoethylcarbamate:The process is performed as in Example 3, starting with 26.5 g ofL-N-Boc-phenylalanine, 22 cm³ of N-methylmorpholine, 13 cm³ of isobutylchloroformate and 10.14 g of N,O-dimethyl-hydroxylamine hydrochloride in300 cm³ of dichloromethane. The product is worked up in an identicalmanner and then purified by chromatography at atmospheric pressure on acolumn of silica gel (particle size 63-200μ; diameter 6 cm; height 25cm), eluting with a dichloromethane/methanol mixture (97/3 by volume).The fractions containing the expected product are collected. Thesefractions are combined and then concentrated under reduced pressure (5kPa) at a temperature in the region of 40° C. 17.1 g of tert-butyl(1S)-1-benzyl-2-[methoxy(methyl)amino]-2-oxoethylcarbamate are obtainedin the form of a colorless oil. (R_(f)=0.65 in a 97/3 by volume mixtureof dichloromethane/methanol, on a Merck 60F₂₅₄ _(^(R)) silica plate).

EXAMPLE 12 (−)-(4S)-4-(4-Aminobutyl)-4,5-dihydro-1,3-thiazol-2-ylaminedihydrochloride

The process is performed as in Example 9, starting with 0.59 g of ethyl(2S)-6-{[(benzyloxy)-carbonyl]amino}-2-{[(tert-butylamino)carbothioyl]-amino}hexanoatein 6 cm³ of 6N hydrochloric acid. After concentration of the reactionmedium under the same conditions, the foam obtained is taken up 3 timesin diethyl ether and the phases are separated each time after settlinghas taken place, and the remaining insoluble material is then taken upin 10 cm³ of acetonitrile. The resulting crystalline product isspin-filtered, washed with hot acetonitrile and then dried under reducedpressure (5 kPa) at a temperature in the region of 20° C. 0.34 g of(−)-(4S)-4-(4-amino-butyl)-4,5-dihydro-1,3-thiazol-2-ylaminedihydro-chloride in the form of cream-colored crystals melting at 170°C. (α_(D) ²⁰=−15.5±0.6 at a concentration of 0.5% in methanol).

Ethyl(2S)-6-{[(benzyloxy)carbonyl]amino}-2-{[(tert-butylamino)carbothioyl]amino}hexanoate:The process is performed as in Example 9, starting with 0.42 g of benzyl(5S)-5-amino-6-hydroxyhexylcarbamate and 0.24 cm³ of tert-butylisothiocyanate in 30 cm³ of ethanol at a temperature in the region of20° C. for 3 days. The reaction is completed by addition of a further0.48 cm³ of isothiocyanate followed by heating for 1 hour at atemperature in the region of 80° C. After an identical work-up, 0.6 g ofethyl(2S)-6-{[(benzyloxy)carbonyl]amino}-2-{[(tert-butylamino)-carbothioyl]amino}hexanoateis obtained in the form of a beige-colored oil with a tendency tocrystallize. (R_(f)=0.62 in a 90/10 by volume mixture ofdichloromethane/methanol, on a Merck 60F₂₅₄ _(^(R)) silica plate).

Benzyl (5S)-5-amino-6-hydroxyhexylcarbamate: A mixture of 4 g of benzyl(5S)-5-{[(tert-butyloxy)carbonyl]amino}-6-hydroxyhexylcarbamate, 30 cm³of trifluoroacetic acid and 20 cm³ of ethanol is stirred at atemperature in the region of 20° C. for 2 hours. After concentration ofthe reaction medium under reduced pressure (5 kPa) at a temperature inthe region of 40° C., the residue obtained is taken up in 50 cm³ ofwater and washed with twice 100 cm³ of diethyl ether. The aqueous phaseis separated out after settling has taken place, basified with sodiumcarbonate to pH 9-10 and then extracted with 3 times 100 cm³ ofdichloromethane. The combined extracts are washed with aqueous sodiumchloride solution and then dried on magnesium sulfate, filtered andconcentrated under reduced pressure (5 kPa) at a temperature in theregion of 40° C. 2.0 g of benzyl (5S)-5-amino-6-hydroxyhexylcarbamateare obtained in the form of a white solid melting at 82° C.

Benzyl (5S)-5-{[(tert-butyloxy)carbonyl]-amino}-6-hydroxyhexylcarbamate:The process is performed as in Example 9, starting with 7 g of methyl(2S)-6-{[(benzyloxy)carbonyl]amino}-2-{[(tert-butyloxy)carbonyl]amino}hexanoatein 70 cm³ of ethanol, 35 cm³ of tetrahydrofuran, 1 g of lithium chlorideand 0.81 g of sodium borohydride. After 16 hours at a temperature in theregion of 20° C., the reaction mass is filtered and the filter cake iswashed with ethanol. The resulting filtrate is concentrated underreduced pressure (5 kPa) at a temperature in the region of 40° C. Afterdissolving the residue obtained in 150 cm³ of dichloromethane, washingwith twice 100 cm³ of aqueous sodium chloride solution and twice 100 cm³of water, drying over magnesium sulfate and finally concentrating underthe same conditions as above, 5.2 g of benzyl(5S)-5-{[(tert-butyloxy)carbonyl]amino}-6-hydroxyhexylcarbamate areobtained in the form of a white solid melting at 67° C.

Methyl(2S)-6-{[benzyloxy)carbonyl]amino}-2-{[(tert-butyloxy)carbonyl]amino}hexanoate:4.8 g of di-tert-butyl dicarbonate are added, under an inert atmosphere,to a stirred solution of 6.6 g of Nε-CBZ-L-lysine methyl esterhydrochloride in 66 cm³ of methanol and 66 cm³ of tetrahydrofuran,cooled to a temperature in the region of 0° C., followed by addition of5.7 cm³ of triethylamine and 10 cm³ of methanol. After stirring themixture at a temperature in the region of 5° C. for 2 hours and then atabout 20° C. for 2 hours, the reaction medium is concentrated underreduced pressure (5 kPa) at a temperature in the region of 40° C. Theresidue obtained is taken up in dichloromethane and the solution iswashed with 100 cm³ of water, dried over magnesium sulfate, filtered andconcentrated under the same conditions as above. 7 g of methyl(2S)-6-{[(benzyloxy)carbonyl]amino}-2-{[(tert-butyloxy)-carbonyl]amino}hexanoateare obtained in the form of a cream-colored oil. (R_(f)=0.90 in a 90/10by volume mixture of dichloromethane/methanol, on a Merck 60F₂₅₄ _(^(R))silica plate).

EXAMPLE 13 (4S,5R)-4-Benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine

The process is performed as in Example 3, starting with 0.7 g ofdiastereoisomer B ofN-(tert-butyl)-N′-((1S)-1-benzyl-2-hydroxypropyl)thiourea which isheated to a temperature in the region of 100° C. for 5 hours in 8.3 cm³of aqueous 6N hydrochloric acid. After concentration of the reactionmedium under reduced pressure (5 kPa) at a temperature in the region of50° C., 50 cm³ of water are added to the residue obtained and thesolution is then extracted with 3 times 25 cm³ of dichloromethane. Theaqueous phase is made alkaline by addition of 0.5 cm³ of 30% causticsoda and extracted with 3 times 50 cm³ of dichloromethane. The extractsare combined, dried over sodium sulfate, filtered and then concentratedunder reduced pressure (5 kPa) at a temperature in the region of 50° C.An oil is obtained, which is purified by chromatography under an argonpressure of 50 kPa, on a column of silica gel (particle size 40-63μ;diameter 2 cm; height 28 cm), eluting with a dichloromethane/methanolmixture (95/5 by volume). The fractions containing the expected productare collected. These fractions are combined and then concentrated underreduced pressure (5 kPa) at a temperature in the region of 40° C. 0.10 gof (4S)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine is obtainedin the form of a pale pink solid melting at 90° C. to become pasty(mixture of diastereoisomers: 82% of cis[(4S,5R)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine] 18% oftrans [(4S,5S)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine]).(R_(f)=0.15 in a 95/5 by volume mixture of dichloromethane/methanol, ona Merck 60F₂₅₄ _(^(R)) silica plate).

EXAMPLE 14 (−)-(4R)-4-Butyl-4,5-dihydro-1,3-thiazol-2-ylamine oxalate

The process is performed as in Example 1, starting with 2.3 g ofN-(tert-butyl)-N′-[(1R)-1-butyl-2-hydroxyethyl]thiourea in 32 cm³ ofaqueous 6N hydrochloric acid. After concentration under reduced pressure(5 kPa) at a temperature in the region of 50° C., the residue obtainedis taken up in 10 cm³ of water and then made alkaline by addition of 2cm³ of 30% caustic soda. After extraction with 3 times 50 cm³ ofdichloromethane, the organic extracts are combined and dried over sodiumsulfate and concentrated under reduced pressure (5 kPa) at a temperaturein the region of 40° C. 1.37 g of a yellow oil are obtained, the oxalateof which is prepared in the following way: starting with 0.3 g of theabove oil in 1 cm³ of acetone, 0.24 g of oxalic acid dissolved in 1 cm³of acetone is added. After precipitation of the salt, the medium isdiluted with 5 cm³ of acetone and filtered. The crystals are washed withtwice 4 cm³ of acetone and then dried in an oven under reduced pressure(10 Pa) at a temperature in the region of 40° C. 0.26 g of(−)-(4R)-4-butyl-4,5-dihydro-1,3-thiazol-2-ylamine oxalate is obtainedin the form of a white solid melting at 91° C. (α_(D) ²⁰=−7 under a 589nm Na lamp and α_(D) ²⁰=−70.1±1.2 under a 365 nm Hg lamp, at aconcentration of 0.5% in methanol).

N-(tert-Butyl)-N′-[(1R)-1-butyl-2-hydroxyethyl]thiourea: The process isperformed as in Example 2, starting with 1.14 g of(2R)-2-amino-2-butyl-1-ethanol and 1.36 cm³ of tert-butyl isothiocyanatein 15 cm³ of ethanol, with stirring for 18 hours at a temperature in theregion of 20° C. and then for 3 hours in the region of 60° C. Afterconcentration of the reaction medium under reduced pressure (5 kPa) at atemperature in the region of 40° C. 2.38 g ofN-(tert-butyl)-N′-[(1R)-1-butyl-2-hydroxyethyl]thiourea are obtained inthe form of a yellow oil. Infrared spectrum (CH₂Cl₂):3620; 4430; 4410;2960; 1560; 1500; 1395; 1375 and 1205 cm⁻¹.

(2R)-2-Aminohexanol: 3.7 g of L-norleucine methyl ester hydrochlorideare dissolved in 20 cm³ of water. The required amount of aqueous sodiumcarbonate solution to obtain a pH of 10 is added to this stirredsolution at a temperature in the region of 20° C. The medium isextracted with 3 times 50 cm³ of ethyl acetate. The extracts arecombined, dried over sodium sulfate, filtered and concentrated underreduced pressure (5 kPa) at a temperature in the region of 50° C. 2.95 gof methyl (2R)-2-amino-2-butylacetate are obtained in the form of ayellow oil. The process is then performed as in Example 2, starting with2.9 g of methyl (2R)-2-amino-2-butylacetate and 1.14 g of sodiumborohydride in 50 cm³ of ethanol. The reaction is carried out at atemperature in the region of −15° C. and the reaction medium is thenstirred for 18 hours at a temperature in the region of 20° C., andfinally for 1 h 30 min at a temperature in the region of 80° C. Afterconcentration of the reaction mass under reduced pressure (5 kPa) at atemperature in the region of 50° C., the residue obtained is purified bychromatography under a pressure of argon (50 kPa) on a column of silicagel (particle size 40-63μ; diameter 2 cm; height 20 cm), eluting with amixture of ethyl acetate/methanol (80/20 by volume). The fractionscontaining the expected product are combined and then concentrated underreduced pressure (5 kPa) at a temperature in the region of 40° C. 1.2 gof (2R)-2-aminohexanol are obtained in the form of an oil which has atendency to crystallize. (α_(D) ²⁰=+2.6±0.4 at a concentration of 0.5%in methanol).

EXAMPLE 15 (+)-(5S)-5-Methyl-4,5-dihydro-1,3-thiazol-2-ylaminehydrochloride

The process is performed as in Example 1, starting with 11.86 g ofN-[(2S)-2-hydroxypropyl]-N′-tert-butylthiourea in 168 cm³ of aqueous 6Nhydrochloric acid. After heating for 3 hours at a temperature in theregion of 100° C. and an identical work-up, 2.30 g of(+)-(5S)-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine hydrochloride areobtained in the form of a white solid melting at 173° C. (α_(D)²⁰=+73.8±1.4 at a concentration of 0.5% in methanol).

N-[(2S)-2-Hydroxypropyl]-N′-tert-butylthiourea: The process is performedas in Example 1, starting with 5 g of (+)-(S)-1-amino-2-propanol and8.43 g of tert-butyl isothiocyanate in 60 cm³ of ethanol. After stirringthe reaction medium for 5 hours at a temperature in the region of 20° C.and then concentration under reduced pressure (5 kPa) at a temperaturein the region of 50° C., the white solid obtained is taken up in diethylether. The suspension is again concentrated under the same conditions asabove. 11.86 g of N-[(2S)-2-hydroxypropyl]-N′-tert-butylthiourea areobtained in the form of a white solid melting at 106° C.

EXAMPLE 16 (−)-(4S)-4-Cyclohexylmethyl-4,5-dihydro-1,3-thiazol-2-ylamine

The process is performed as in Example 1, starting with 11.1 g ofN-(tert-butyl)-N′-[(1S)-1-cyclohexylmethyl-2-hydroxyethyl]thiourea in110 cm³ of aqueous 6N hydrochloric acid maintained at a temperature inthe region of 100° C. for 2 hours. By means of an identical work-up, 3.6g of (−)-(4S)-4-cyclohexylmethyl-4,5-dihydro-1,3-thiazol-2-ylamine areobtained in the form of a white solid melting at 169° C. (α_(D)²⁰=−33.9±0.8 at a concentration of 0.5% in methanol).

N-(tert-Butyl)-N′-[(1S)-1-cyclohexylmethyl-2-hydroxyethyl]thiourea: Theprocess is performed as in Example 3, starting with 8.1 g of(+)-(2S)-2-amino-3-cyclohexyl-1-propanol and 9.8 cm³ of tert-butylisothiocyanate in 79 cm³ of ethanol. The reaction medium is stirred for72 hours at a temperature in the region of 20° C. After concentration ofthe reaction mass under reduced pressure (5 kPa) at a temperature in theregion of 50° C., the oil obtained is taken up in 110 cm³ of coldpetroleum ether. The crystals are filtered off and dried under reducedpressure (10 Pa) at a temperature in the region of 60° C. 11.1 g ofN-(tert-butyl)-N′-[(1S)-1-cyclohexylmethyl-2-hydroxyethyl]thiourea areobtained in the form of a white solid melting at 97° C.

EXAMPLE 17 (+)-(4R)-4-Cyclohexylmethyl-4,5-dihydro-1,3-thiazol-2-ylaminehydrochloride

The process is performed as in Example 1, starting with 2.9 g ofN-(tert-butyl)-N′-[(1R)-1-cyclohexylmethyl-2-hydroxyethyl]thiourea in 28cm³ of aqueous 6N hydrochloric acid by heating at a temperature in theregion of 100° C. for 2 h 15 min. By means of an identical work-up, asolid is obtained which is purified by dissolution in 15 cm³ of waterand extraction with 10 cm³ of dichloromethane. The aqueous phase is madealkaline by addition of 10 cm³ of 1N sodium hydroxide and is extractedwith twice 15 cm³ of ethyl acetate. The combined organic extracts areconcentrated under reduced pressure (5 kPa) at a temperature in theregion of 40° C. The resulting paste is taken up in twice 20 cm³ ofdiethyl ether. The solid is filtered off and dried in an oven underreduced pressure (10 Pa) at a temperature in the region of 60° C. 0.4 gof (+)-(4R)-4-cyclohexylmethyl-4,5-dihydro-1,3-thiazol-2-ylaminehydrochloride is obtained in the form of a white solid melting at 169°C. (α_(D) ²⁰=+31.8±0.9 at a concentration of 0.5% in methanol).

N-(tert-Butyl)-N′-[(1R)-1-cyclohexylmethyl-2-hydroxyethyl]thiourea: Theprocess is performed as in Example 3, starting with 4.89 g of(2R)-2-amino-3-cyclohexyl-1-propanol and 5.9 cm³ of tert-butylisothiocyanate in 48 cm³ of absolute ethanol. After stirring for 5 daysat a temperature in the region of 20° C., the reaction medium isconcentrated under reduced pressure (5 kPa) at a temperature in theregion of 40° C. The solid obtained is taken up in 200 cm³ of petroleumether and the insoluble material is then filtered off and air-dried.2.96 g ofN-(tert-butyl)-N′-[(1R)]-1-cyclohexylmethyl-2-hydroxyethyl]thiourea areobtained in the form of a white solid. (R_(f)=0.29 in an ethylacetate/cyclohexane mixture, on a Merck 60F₂₅₄ _(^(R)) silica plate).

(2R)-2-Amino-3-cyclohexyl-1-propanol: The process is performed as inExample 1, starting with 6.2 g of ethyl(2R)-2-amino-3-cyclohexylpropionate and 1.93 g of sodium borohydride in120 cm³ of absolute ethanol at about 5° C. for 10 minutes. The medium iswarmed to room temperature and stirred for a further 3 h 30 minutes.After cooling again to about 5° C. and addition of a further 40.94 g ofborohydride, followed by stirring at a temperature in the region of 20°C. for 65 hours, the reaction medium is concentrated under reducedpressure (5 kPa) at a temperature in the region of 40° C. A solid isobtained, which is purified by chromatography under a pressure of argon(100 kPa) on a column of silica gel (particle size 40-63μ; 320 g),eluting with pure methanol. The fractions containing the expectedproduct are collected. These fractions are combined and thenconcentrated under reduced pressure (5 kPa) at a temperature in theregion of 40° C. 5.16 g of (2R)-2-amino-3-cyclohexyl-1-propanol areobtained in the form of a sticky white solid. (R_(f)=0.25 in methanol ona Merck 60F₂₅₄ _(^(R)) silica plate).

Ethyl (2R)-2-amino-3-cyclohexylpropionate: The process is performed asin Example 2, starting with 10 g of β-cyclohexyl-(D)-alaninehydrochloride in 96 cm³ of absolute ethanol, by treating it with astream of dry hydrogen chloride at a temperature in the region of 0° C.for 20 minutes. After heating to about 80° C. for 4 days, followed bycooling to 0° C., the mixture is again treated with a stream of hydrogenchloride for 20 minutes, followed by heating to a temperature in theregion of 80° C. for 20 hours. The reaction medium is concentrated underreduced pressure (5 kPa) at a temperature in the region of 40° C., andthe residue obtained is dissolved in 200 cm³ of water, made alkaline byaddition of 19 g of solid potassium carbonate. After evaporation, theresulting solid is taken up in 200 cm³ of ethanol at a temperature inthe region of 80° C. The insoluble material is filtered off and thefiltrate is evaporated under reduced pressure (5 kPa) at a temperaturein the region of 40° C. The residue obtained is taken up in 130 cm³ ofethanol at room temperature. The insoluble material is filtered off andthe filtrate is again evaporated under the same conditions as above. 4.8g of ethyl (2R)-2-amino-3-cyclohexylpropionate are obtained in the formof a whitish paste. (R_(f)=0.80 in a 90/10 by volume mixture ofethanol/aqueous ammonia, on a Merck 60F₂₅₄ _(^(R)) silica plate).

EXAMPLE 18 4-(3-Nitrophenyl)-4,5-dihydro-1,3-thiazol-2-ylamine

The process is performed as in Example 2, starting with 1.49 g ofN-(tert-butyl)-N′-[2-hydroxy-1-(3-nitrophenyl)ethyl]thiourea in 14 cm³of aqueous 6 N hydrochloric acid by heating to a temperature in theregion of 100° C. for 2 h 30 min. By means of an identical work-up, 1.01g of 4-(3-nitrophenyl)-4,5-dihydro-1,3-thiazol-2-ylamine are obtained inthe form of a cream-colored solid melting at 232° C.

EXAMPLE 19(+)-(4R)-4-(4-Pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylaminedihydrochloride

The process is performed under the conditions of Example 1 starting with0.46 g ofN-(tert-butyl)-N′-[(1R)-2-hydroxy-1-(4-pyridylmethyl)ethyl]thioureawhich is heated in 5 cm³ of aqueous 5 N hydrochloric acid for 16 hoursat a temperature in the region of 100° C. After concentration of thereaction mass under reduced pressure (5 kPa) at a temperature in theregion of 40° C., an oil is obtained which is taken up in 3 cm³ of2-propanol. The resulting crystalline precipitate is spin-filtered,washed with 2-propanol and air-dried. 0.1 g of(+)-(4R)-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylaminedihydrochloride is obtained in the form of an orange-colored solidmelting at 150° C. (α_(D) ²⁰=+38.3±0.9 at a concentration of 0.5% inMeOH).

N-(tert-Butyl)-N′-[(1R)-2-hydroxy-1-(4-pyridylmethyl)ethyl]thiourea: Asolution of 0.1 g of tert-butyl(1R)-1-(4-pyridylmethyl)-2-hydroxyethyl-carbamate in 3 cm³ of 4 Nhydrochloric dioxane is stirred for 16 hours at a temperature in theregion of 20° C. The reaction mass is concentrated under reducedpressure (5 kPa) at a temperature in the region of 40° C. 0.075 g of awhite product is obtained, and is dissolved in 4 cm³ of ethanol. Afteraddition of 0.08 cm³ of triethylamine and then 0.09 cm³ of tert-butylisothiocyanate, the mixture is stirred for 16 hours at a temperature inthe region of 20° C. and then for 6 hours at a temperature in the regionof 50° C. The mixture is evaporated under reduced pressure (5 kPa) at atemperature in the region of 40° C. and the residue obtained is thentriturated from 20 cm³ of water. The water is separated out aftersettling has taken place, ethanol is added to the resulting oil and thesolution is then concentrated under the above conditions. 0.10 g ofN-(tert-butyl)-N′-[(1R)-2-hydroxy-1-(4-pyridylmethyl)ethyl]thiourea isobtained in the form of an orange-colored oil. (R_(f)=0.50 in a 4/1/1 byvolume mixture of ethyl acetate/acetic acid/water, on a Merck 60F₂₅₄_(^(R)) silica plate).

Tert-Butyl (1R)-1-(4-pyridylmethyl)-2-hydroxyethylcarbamate: 0.52 cm³ oftriethylamine is added to a stirred mixture of 1 g ofBoc-D-4-pyridylalanine in 10 cm³ of tetrahydrofuran, under an inertatmosphere, and the mixture is then cooled to a temperature in theregion of −18° C. After addition of 0.47 cm³ of isobutyl chloroformate,stirring is continued for 30 minutes at a temperature of between −18° C.and −10° C. The mixture is rapidly filtered, followed by addition to thefiltrate of 0.28 g of sodium borohydride predissolved in 2 cm³ of water.The mixture is stirred for 1 hour at a temperature in the region of 0°C. and then for 16 hours at a temperature in the region of 20° C. Themixture is made alkaline by addition of aqueous potassium carbonatesolution and then stirred in the presence of ethyl acetate. The organicphase is separated out after settling has taken place and then washedwith water, dried over magnesium sulfate, filtered and concentratedunder reduced pressure (5 kPa) at a temperature in the region of 40° C.The residue obtained is purified by chromatography under an argonpressure of 50 kPa on a column of silica gel (particle size 40-63μ:diameter 2.2 cm; height of silica 30 cm), eluting first with ethylacetate alone and collecting 30-cm³ fractions. Fractions 1 to 18 arediscarded and the column is then eluted with a mixture of ethylacetate/methanol (90/10 by volume). Fractions 23 to 26 are collected andthen combined. After concentration under reduced pressure (5 kPa) at atemperature in the region of 40° C., 0.10 g of tert-butyl(1R)-1-(4-pyridylmethyl)-2-hydroxy-ethylcarbamate is obtained in theform of an oil. Infrared spectrum (CH₂Cl₂): 3618; 3434; 2981; 1708;1501; 1367; 1168 and 1057 cm⁻¹.

EXAMPLE 20(+)-(4R,5R)-5-Methyl-(4R,5R)-4-(4-pyridylmethyl)-4,5-dihydrothiazol-2-ylaminedihydrochloride

A suspension of 1.96 g ofN-tert-butyl-N′-[1R,2RS)-1-(4-pyridylmethyl)-2-hydroxypropyl]-thioureain 25 cm³ of 5N hydrochloric acid is heated at a temperature in theregion of 100° C. for 18 hours. The reaction medium is concentratedunder reduced pressure (2 kPa) at a temperature in the region of 40° C.The residue obtained is purified by chromatography on a Chiralcel OD 20μcolumn in a heptane/isopropanol/triethylamine mixture (90/10/0.1 byvolume). The fractions containing the expected product are concentratedunder reduced pressure (1 kPa) at a temperature in the region of 40° C.The residue obtained is purified by chromatography at atmosphericpressure on a column of silica gel (particle size 40-60 μm; diameter 1.2cm; height 30 cm), eluting with a mixture of ethyl acetate/aceticacid/water (2/1/1 by volume). The fractions containing the expectedproduct are combined and concentrated under reduced pressure (2 kPa) ata temperature in the region of 40° C. The residue obtained is taken upin 5 cm³ of 5N hydrochloric acid and ethanol and is then concentratedunder reduced pressure (2 kPa) at a temperature in the region of 40° C.After drying in a desiccator under reduced pressure (0.1 kPa) at atemperature in the region of 40° C., 0.4 g of(+)-(4R,5R)-4-(4-pyridylmethyl)-5-methyl-4,5-dihydrothiazol-2-ylaminedihydrochloride is obtained in the form of a highly hygroscopic foam [¹HNMR spectrum (300 MHz, (CD₃)₂SO-d₆, δ in ppm): 1.44 (d, J=7 Hz: 3H);3.22 (dd, J=13.5 and 7.5 Hz: 1H); 3.32 (dd, J=13.5 and 5 Hz: 1H); 3.90(mt: 1H); 4.37 (mt: 1H); 8.01 (broad d, J=6 Hz: 2H); 8.88 (broad d, J=6Hz: 2H); 9.34 (broad s: 1H); 9.85 (broad s: 1H); 10.31 (unresolvedcomplex: 1H); (a_(D) ²⁰=+75.3+/−1.3 in 0.5% methanol).

N′-tert-Butyl-N′[(1R,2RS)-1(4-pyridylmethyl)-2-hydroxypropyl]thiourea: asolution of 1.41 g of (3R,2RS)-3-amino-4-(4-pyridinyl)-2-butanol in 30cm³ of ethanol, to which are added 1.08 cm³ of tert-butyl isothiocyanateand then 2.16 cm³ of triethylamine, is heated for 16 hours with stirringat a temperature in the region of 50° C. The reaction medium isconcentrated under reduced pressure (2 kPa) at a temperature in theregion of 40° C., taken up in 10 cm³ of water, washed with twice 30 cm³of dichloromethane, dried over magnesium sulfate, filtered, evaporatedunder the above conditions and then dried in a desiccator under reducedpressure (0.1 kPa) at a temperature in the region of 40° C. 2 g ofN′-tert-butyl-N′-[(1R,2RS)-1-(4-pyridyl-methyl)-2-hydroxypropyl]thioureaare obtained in the form of an orange-colored oil [¹H NMR spectrum (300MHz, (CD₃)₂SO-d₆, δ in ppm). We observe a mixture of twodiastereoisomers A and B in respective proportions of 70/30, δ=0.99 (d,J=6.5 Hz: 0.9H); 1.09 (d, J=6.5 Hz: 2.1H); 1.37 (s: 6.3H); 1.41 (s:2.7H); 2.74 (dd, J=14.5 and 9 Hz: 0.7H); from 2.75 to 2.90 (mt: 0.6H);2.93 (dd, J=14.5 and 5 Hz: 0.7H); from 3.55 to 3.80 (mt: 1H); from 4.35to 4.60 (unresolved complex: 1H; 4.65 (unresolved complex: 0.3H); 4.88(unresolved complex: 0.7H); from 7.10 to 7.25 (mt: 1H); 7.17 (broad s:0.7H); 7.27 (broad d, J=6 Hz: 1.4H); 7.31 (broad d, J=6 Hz: 0.6H); 7.44(broad s: 0.3H); from 8.35 to 8.50 (mt: 2H).

(3R,2RS)-3-Amino-4-(4-pyridyl)-2-butanol dihydrochloride: a solution of20 cm³ of 4N hydrochloric acid in dioxane is added with stirring, at atemperature in the region of 20° C., to a solution of 1.85 g oftert-butyl N-[(1R,2RS)-1-(4-pyridylmethyl)-2-hydroxypropyl]carbamate.The mixture is stirred at a temperature in the region of 20° C. for 5hours and is then concentrated under reduced pressure (2 kPa) at atemperature in the region of 40° C. 1.8 g of(3R,2RS)-3-amino-4-(4-pyridyl)-2-butanol dihydrochloride are obtained inthe form of a yellow solid [¹H NMR spectrum (300 MHz, (CD₃)₂SO-d₆ withaddition of a few drops of CD₃COOD-d₄, δ in ppm). We observe a mixtureof two diastereoisomers A and B in respective proportions of 70/30;δ=1.18 and 1.20 (2 d, J=6.5 Hz: 3H in total); 3.13 (dd, J=10.5 and 6 Hz:0.7H); from 3.20 to 3.35 (mt: 1.3H); from 3.45 to 3.65 (mt: 0.6H); 3.72(mt: 0.7H); 3.96 (mt: 0.7H); from 8.05 to 8.15 (mt: 2H); 8.88 (broad d,J=6 Hz: 2H)].

Tert-Butyl N-[(1R,2RS)-1-(4-pyridylmethyl)-2-hydroxy-propyl]carbamate:0.43 g of sodium borohydride is added, with stirring and at atemperature in the region of 10° C., to a solution of 2 g of tert-butylN-[(1R)-1-(4-pyridylmethyl-2-oxopropyl]carbamate and the mixture is thenstirred at a temperature in the region of 20° C. for 18 hours. Thereaction medium is concentrated under reduced pressure (1 kPa) at atemperature in the region of 40° C., taken up in 50 cm³ of water,extracted with 100 cm³ of ethyl acetate, dried over magnesium sulfate,filtered and concentrated under reduced pressure (1 kPa) at atemperature in the region of 40° C. 1.83 g of tert-butylN-[(1R,2RS)-1-(4-pyridylmethyl)-2-hydroxy-propyl]carbamate are obtainedin the form of a yellow solid [¹H NMR spectrum (300 MHz, (CD₃)₂SO-d₆, δin ppm). We observe a mixture of two diastereoisomers A and B inrespective proportions of 70/30; δ=1.03 (d, J=6.5 Hz: 0.9H); 1.09 (d,J=6.5 Hz: 2.1H); 1.28 (s:2.7H); 1.30 (s, 6.3H); from 2.45 to 2.55 (mt:0.7H); 2.61 (dd, J=13.5 and 10.5 Hz: 0.3H); 2.81 (dd, J=13.5 and 4 Hz0.3H); 3.01 (dd, J=13.5 and 2 Hz: 0.7H); from 3.40 to 3.70 (mt: 2H);4.70 (d, J =5.5 Hz: 0.3H); 4.78 (d, J=5.5 Hz: 0.7H); 6.53 (d, J =9 Hz:0.3H); 6.67 (d, J=9 Hz: 0.7H); 7.20 (broad d, J=6 Hz: 1.4H); 7.25(broad, J=6 Hz: 0.6H); from 8.40 to 8.50 (mt: 2H)].

Tert-Butyl N-[(1R)-1-(4-pyridylmethyl)-2-oxopropyl]carbamate: a mixture,under an inert atmosphere, of 5.3 g ofN-{2-[N-methoxy-N-(methyl)-amino]-2-oxo-(1R)-1-(4-pyridylmethyl)ethyl}carbamatein 120 cm³ of tetrahydrofuran is cooled to a temperature in the regionon 0° C. 17 cm³ of a 3M solution of methylmagnesium bromide in diethylether are then added over 1 hour and the mixture is stirred for 1 hourat 0° C. and for 18 hours at a temperature in the region of 20° C. Thereaction medium is cooled again to a temperature in the region of 0° C.,followed by dropwise addition of 30 cm³ of 1N hydrochloric acid and 100cm³ of water, the resulting mixture is extracted with ethyl acetate andthe extracts are washed with twice 100 cm³ of water. The combinedorganic phases are dried over sodium sulfate, filtered and thenconcentrated under reduced pressure (2 kPa) at a temperature in theregion of 40° C. The residue obtained is purified by chromatography atatmospheric pressure on a column of silica gel (particle size 60-200 μm;diameter 4 cm; height 35 cm), eluting with ethyl acetate. The fractionscontaining the expected product are combined and concentrated underreduced pressure (2 kPa) at a temperature in the region of 40° C. 0.2 gof tert-butyl N-[(1R,2RS)-1-(4-pyridylmethyl)-2-oxopropyl]carbamate isobtained [¹H NMR spectrum (300 MHz, (CD₃)₂SO-d₆, δ in ppm): 1.34 (s:9H); 2.16 (s: 3H); 2.71 (dd, J=14 and 10,5 Hz: 1H); 3.08 (dd, J=14 and4.5 Hz); 4.21 (mt: 1H); 7.27 (broad d, J=5.5 Hz: 2H); 7.34 (d, J=8 Hz:1H); 8.47 (broad d, J=5.5 Hz: 2H)].

Tert-ButylN-{2-[N-methoxy-N-(methyl)amino]-2-oxo-(1R)-1-(4-pyridylmethyl)ethyl}carbamate:a solution, under an inert atmosphere, of 20 g of D-N-Boc-pyridylalanineand 16.5 cm³ of N-methylmorpholine in 500 cm³ of dichloromethane iscooled to a temperature in the region of −15° C. 9.75 cm³ of isobutylchloroformate are then added and the mixture is stirred for 15 minutesat this temperature. After addition of 7.61 g ofN,O-dimethylhydroxylamine hydrochloride, stirring is continued for 1hour at a temperature in the region of −15° C. and then for 18 hours atroom temperature. 250 cm³ of water are added to the reaction medium,followed by extraction with 100 cm³ of dichloromethane. The organicphase is dried over sodium sulfate, filtered and concentrated underreduced pressure (2 kPa) at a temperature in the region of 50° C. Theresidue is purified on a column of silica gel (particle size 60-200 μm;height 35 cm), eluting with ethyl acetate. The fractions containing theexpected product are combined and concentrated under reduced pressure (2kPa) at a temperature in the region of 40° C. 6.5 g of tert-butylN-{2-[N-methoxy-N-(methyl)-amino]-2-oxo-(1R)-1-(4-pyridylmethyl)ethyl}carbamateare obtained in the form of a thick yellow oil [¹H NMR spectrum (300MHz, (CD₃)₂SO-d₆, δ in ppm): 1.33 (s: 9H); 2.78 (dd, J=13.5 and 10 Hz:1H); 2.89 (dd, J=13.5 and 4.5 Hz: 1H); 3.14 (broad s: 3H); 3.76 (broads: 3H); 4.63 (mt: 1H); 7.24 (mt: 1H); 7.27 (broad d, J=5.5 Hz: 2H); 8.48(broad d, J=5.5 Hz: 2H)].

EXAMPLES 21 and 22 (+)-4-(5-Thiazolylmethyl)4,5-dihydrothiazol-2-ylaminedihydrochloride and(−)-4-(5-thiazolylmethyl)4,5-dihydrothiazol-2-ylamine dihydrochloride

A racemic mixture of 0.38 g of(4RS)-4-(5-thiazolylmethyl)-4,5-dihydrothiazol-2-ylamine dihydrochlorideis separated on a Chiralcel OD 10μ column in a mixture ofheptane/2-isopropanol/triethylamine (80/20/0.1 by volume). The fractionscontaining the expected product are concentrated under reduced pressure(1 kPa) at a temperature in the region of 40° C. to give 0.053 g of(+)-4-(5-thiazolylmethyl)4,5-dihydrothiazol-2-ylamine dihydrochlorideand 0.057 g of (−)-4-(5 thiazolylmethyl)4,5-dihydrothiazol-2-ylaminedihydrochloride.

(+)-4-(5-Thiazolylmethyl)4,5-dihydro-thiazol-2-ylamine dihydrochloride:¹H NMR spectrum (300 MHz, (CD₃)₂SO-d₆, δ in ppm): from 3.20 to 3.40 (mt:3H); 3.70 (dd, J=11.5 and 8 Hz: 1H); 4.58 (mt: 1H); 7.85 (s: 1H); 9.10(s: 1H); 9.26 (unresolved complex: 1H); 9.67 (unresolved complex: 1H);10.13 (broad s: 1H).

(−)-4-(5-Thiazolylmethyl)4,5-dihydro-thiazol-2-ylamine dihydrochloride:¹H NMR spectrum (300 MHz, (CD₃)₂SO-d₆, δ in ppm): from 3.20 to 3.40 (mt:3H); 3.70 (dd, J=12 and 8 Hz: 1H); 4.58 (mt: 1H); 7.85 (s: 1H); 9.10 (s:1H); 9.26 (unresolved complex: 1H); 9.67 (unresolved complex: 1H); 10.14(broad s, 1H); α_(D) ²⁰=−4.2+/−0.6 at a concentration of 0.5% inmethanol).

(4RS)-4-(5-Thiazolylmethyl)-4,5-dihydro-thiazol-2-ylaminedihydrochloride: a solution of 0.56 g ofN-(tert-butyl)-N′-[(1RS)-1-hydroxymethyl-2-(5-thiazolyl)ethyl]thioureain 5.5 cm³ of 6N hydrochloric acid is heated at a temperature in theregion of 110° C. for 3 hours. The reaction medium is concentrated underreduced pressure (1 kPa) at a temperature in the region of 60° C., takenup in 4 cm³ of ethanol and 6 cm³ of diethyl ether and evaporated underthe same conditions as above. The residue is taken up in 6 cm³ ofethanol and filtered, and the solid is dried in a desiccator underreduced pressure (0.1 kPa) at a temperature in the region of 40° C. andthen dissolved in 5.5 cm³ of 6N hydrochloric acid solution and refluxedat a temperature in the region of 110° C. for 9 hours. The reactionmedium is concentrated under reduced pressure (1 kPa) at a temperaturein the region of 40° C. and dried in a desiccator under reduced pressure(0.1 kPa) at a temperature in the region of 40° C., to give 0.54 g of(4RS)-4-(5-thiazolylmethyl)-4,5-dihydro-thiazol-2-ylaminedihydrochloride in the form of a pasty solid [¹HNMR spectrum (300 MHz,(CD₃)₂SO-d₆, δ in ppm): from 3.20 to 3.40 (mt: 3H); from 3.60 to 3.80(mt: 1H); 4.57 (mt: 1H); 7.85 (s, 1H); 9.10 (s: 1H); 9.26 (unresolvedcomplex: 1H); 9.66 (unresolved complex: 1H); 10.13 (broad s: 1H].

N-(tert-Butyl)-N′-[(1RS)-1-hydroxymethyl-2-(5-thiazolyl)ethyl]thiourea:0.52 cm³ of triethylamine is added to a solution of 0.56 g of(2RS)-2-amino-3-(5-thiazolyl)-1-propanol hydrochloride in 8 cm³ ofethanol, followed by addition of 0.55 cm³ of tert-butyl isothiocyanate.The mixture is stirred at a temperature in the region of 20° C. for 18hours and is then heated at a temperature in the region of 60° C. for 1hour 30 minutes. After cooling, the reaction medium is concentratedunder reduced pressure (1 kPa) at a temperature in the region of 40° C.,taken up in 6 cm³ of water and washed with 3 times 20 cm³ ofdichloromethane, dried over magnesium sulfate, filtered, evaporatedunder the above conditions and then dried in a desiccator under reducedpressure (0.1 kPa) at a temperature in the region of 40° C. 0.56 g ofN′-(tert-butyl-N[prime]-[(1RS)-1-hydroxymethyl-2-(5-thiazolyl)ethyl]-thioureais obtained in the form of a viscous yellow oil [¹H NMR spectrum (300MHz, (CD₃)₂SO-d₆, δ in ppm): 1.43 (s: 9H); 3.03 (dd, J=15 and 7 Hz: 1H);3.19 (dd, J=15 and 7 Hz: 1H); from 3.30 to 3.50 (mt: 2H); 4.41 (mt: 1H);4.97 (t, J=5 Hz: 1H); 7.23 (d, J=8 Hz: 1H); 7.30 (broad s: 1H); 7,67 (s:1H); 8.94 (s: 1H)].

(2RS)-2-Amino-3-(5-thiazolyl)-1-propanol hydrochloride: a solution of0.63 g of N-[(1RS)-1-hydroxymethyl-2-(5-thiazolyl)ethyl]acetamide in7.86 cm³ of 6N hydrochloric acid is heated to a temperature in theregion of 110° C. for 3 hours. The reaction mixture is filtered,concentrated under reduced pressure (1 kPa) at a temperature in theregion of 40° C., taken up in isopropyl ether, concentrated under theabove conditions, taken up in 10 cm³ of isopropyl ether, filtered anddried in a desiccator under reduced pressure (0.1 kPa) at a temperaturein the region of 40° C. 0.56 g of(2RS)-2-amino-3-(5-thiazolyl)-1-propanol hydrochloride is obtained inthe form of a beige-colored solid melting at 192° C. [¹H NMR spectrum(300 MHz, (CD₃)₂SO-d₆, δ in ppm): 3.21 (d, J=7 Hz: 2H); 3.35 (mt: 1H);3.48 (dd, J=11.5 and 5.5 Hz: 1H); 3.61 (dd, J=11.5 and 4 Hz: 1H); 7.83(broad s: 1H); 8.19 (unresolved complex: 3H); 9.10 (broad s: 1H)].

N-[(1RS)-1-Hydroxymethyl-2-(5-thiazolyl)-ethyl]acetamide: 0.4 g ofsodium borohydride is added to a solution of 1.2 g of ethyl(2RS)-2-acetylamino-3-(5-thiazolyl)propanoate in 20 cm³ of ethanol,followed by stirring under an inert atmosphere at a temperature in theregion of 20° C. After 18 hours, a further 0.1 g of sodium borohydrideis added and the mixture is then stirred for 24 hours at a temperaturein the region of 20° C. The reaction medium is concentrated underreduced pressure (1 kPa) at a temperature in the region of 40° C. Theresidue is taken up in 10 cm³ of water and extracted with 3 times 30 cm³of ethyl acetate. The organic phase is dried over magnesium sulfate,filtered and concentrated under reduced pressure (1 kPa) at atemperature in the region of 40° C. The residue is chromatographed underan argon pressure of 60 kPa on a column of silica gel (particle size40-63μ; diameter 3.5 cm; height 31 cm), eluting with 100 cm³ ofdichloromethane, 600 cm³ of a dichloromethane/methanol mixture (98/2 byvolume), 500 cm³ of a dichloromethane/methanol mixture (96/4 by volume)and 1 dm³ of a dichloromethane/methanol mixture (90/10 by volume). Thefractions containing the expected product are combined and thenconcentrated under the above conditions. 0.63 g ofN-[(1RS)-1-hydroxymethyl-2-(5-thiazolyl)-ethyl]acetamide is obtained inthe form of a yellow oil [¹H NMR spectrum (300 MHz, (CD₃)₂SO-d₆, δ inppm): 1.80 (s: 3H); 2.85 (dd, J=15 and 9 Hz: 1H); 3.16 (dd, J=15 and 5Hz: 1H); from 3.25 to 3.45 (mt: 2H); 3.87 (mt: 1H); 4.85 (mt: 1H); 7.65(S: 1H); 7.79 (d, J=8.5 Hz: 1H); 8.91 (s: 1H)].

Ethyl (2RS)-2-acetylamino-3-(5-thiazolyl)-propanoate: 2.7 cm³ of 6Nsodium hydroxide are added dropwise to a solution of 3.3 g of diethyl2-acetyl-amino-2-(5-thiazolylmethyl)malonate in 70 cm³ of ethanol. Themixture is stirred for 5 hours, followed by dropwise addition of 1.5 cm³of 12N hydrochloric acid; a precipitate forms. The product isconcentrated under reduced pressure (1 kPa) at a temperature in theregion of 40° C. to give a brown solid which is dried for 12 hours in adesiccator under reduced pressure (0.1 kPa) at a temperature in theregion of 40° C. This residue is taken up in 50 cm³ of dioxane and thenheated at a temperature in the region of 100° C. for 3 hours 30 minutes.The reaction medium is evaporated under reduced pressure (1 kPa) at atemperature in the region of 40° C. The residue is chromatographed underan argon pressure of 60 kPa on a column of silica gel (particle size40-63μ; diameter 3.5 cm; height 31 cm), eluting with 675 cm³ ofdichloromethane, 500 cm³ of a dichloromethane/methanol mixture (99/1 byvolume), 500 cm³ of a dichloromethane/methanol mixture (98/02 byvolume), 500 cm³ of a dichloromethane/methanol mixture (97/3 by volume),500 cm³ of a dichloromethane/methanol mixture (95/5 by volume), 500 cm³of a dichloromethane/methanol/aqueous ammonia mixture (12/1.5/0.5 byvolume) and 500 cm³ of a dichloromethane/methanol/aqueous ammoniamixture (12/3/0.5 by volume). The fractions containing the expectedproduct are combined and then concentrated under the above conditions.0.8 g of ethyl (2RS)-2-acetylamino-3-(5-thiazolyl)propanoate is obtainedin the form of brown oil [Mass spectrum: DCI m/z=243 MH⁺].

Diethyl 2-acetylamino-2-(5-thiazolylmethyl)-malonate: after dissolving1.24 g of sodium in 20 cm³ of ethanol, 10.86 cm³ of diethylacetamidomalonate are added, followed by heating at a temperature in theregion of 75° C. After 15 minutes, a solution of 5-chloromethylthiazolein 20 cm³ of ethanol is added, followed by heating for 2 hours at atemperature in the region of 75° C. The reaction medium is evaporatedunder reduced pressure (1 kPa) at a temperature in the region of 40° C.The residue is chromatographed under an argon pressure of 60 kPa on acolumn of silica gel (particle size 60-200μ; diameter 6.5 cm; height 40cm), eluting with a dichloromethane/methanol mixture (99/1 by volume), adichloromethane/methanol mixture (98/02 by volume) and then adichloromethane/methanol mixture (95/5 by volume). The fractionscontaining the expected product are combined and then concentrated underthe above conditions. 3.3 g of diethyl2-acetylamino-2-(5-thiazolylmethyl)malonate are obtained in the form ofan orange-colored solid [¹H NMR spectrum (300 MHz, (CD₃)₂SO-d₆, δ inppm): 1.18 (t, J=7.5 Hz: 6H); 2.00 (s: 3H); 3.75 (s: 2H); 4.17 (q, J=7.5Hz: 4H); 7.61 (s: 1H); 8.37 (broad s: 1H); 9.00 (s: 1H)].

5-Chloromethylthiazole: 11 g of N-chloro-succinimide are added to asolution of 8.2 g of 5-methylthiazole in 250 cm³ of carbontetrachloride, followed by addition of 0.1 g of benzoyl peroxide. Themixture is heated for 20 hours at a temperature in the region of 80° C.and is then exposed to UV for 5 hours. The reaction mixture is cooled,filtered and concentrated under reduced pressure (1 kPa) at atemperature in the region of 20° C. 6.4 g of 5-chloro-methylthiazole areobtained [Mass spectrum: DCI m/z=134 MH⁺].

EXAMPLE 23 (+)-(4R)-4-(2-Pyrazinylmethyl)-4,5-dihydro-2-thiazolyl-aminedihydrochloride

A racemic mixture of 2.9 g of(4RS)-4-(2-pyrazinylmethyl)-4,5-dihydro-2-thiazolyl-aminedihydrochloride is separated on a Chiralcel OD10μ column in aheptane/ethanol/triethylamine mixture (80/20/0.1 by volume). Thefractions containing the expected product are concentrated under reducedpressure (1 kPa) at a temperature in the region of 40° C. The residueobtained is dissolved in 5 cm³ of ethanol, followed by addition of 6 cm³of hydrochloric acid dissolved in diethyl ether and 15 cm³ of diethylether. After filtration, washing with 15 cm³ of diethyl ether anddrying, 0.371 g of(+)-(4R)-4-(2-pyrazinyl-methyl)-4,5-dihydro-2-thiazolylaminedihydrochloride is obtained in the form of a beige-colored solid meltingat 154° C. [¹H NMR spectrum (300 MHz, (CD₃)₂SO-d₆, δ in ppm): 3.22 (d,J=6.5 Hz: 2H); 3.45 (dd, J=11.5 and 5.5 Hz: 1H); 3.75 (dd, J=11.5 and 8Hz: 1H); 4.73 (mt: 1H); 8.60 (broad d, J=2.5 Hz: 1H); 8.63 (dd, J=2.5and 1.5 Hz: 1H); 8.66 (broad s; 1H); 9.09 (unresolved complex: 1H); 9.58(unresolved complex: 1H); 9.95 (broad s: 1H); (α_(D) ²⁰=+46.3+/−1.1 at aconcentration of 0.5% in methanol)].

(4RS)-4-(2-Pyrazinylmethyl)-4,5-dihydro-2-thiazolylaminedihydrochloride: A solution of 7.2 g ofN-(tert-butyl)-N′-[(1RS)-1-hydroxymethyl-2-(2-pyrazinyl)ethyl]thioureain 20 cm³ of 5N hydrochloric acid is heated at a temperature in theregion of 110° C. for 20 hours. The reaction medium is concentratedunder reduced pressure (1 kPa) at a temperature in the region of 55° C.and then taken up in ethanol and concentrated under the same conditionsas above. The residue is chromatographed at atmospheric pressure on acolumn of silica gel (particle size 40-60μ; diameter 4 cm; height 30cm), eluting with an acetic acid/water/ethyl acetate mixture (1/1/4 byvolume). The fractions containing the expected product are combined andthen concentrated under the above conditions. The oil obtained is takenup in ethanol and the precipitate obtained is filtered off and thendried in a desiccator under reduced pressure (0.1 kPa) at a temperaturein the region of 40° C. to give 2.9 g of(4RS)-4-(2-pyrazinylmethyl)-4,5-dihydro-1,3-thiazol-2-ylaminedihydrochloride in the form of a brown solid melting at 190° C. [¹H NMRspectrum (300 MHz, (CD₃)₂SO-d₆, δ in ppm): 3.23 (d, J=6 Hz: 2H); 3.43(dd, J=11.5 and 5.5 Hz: 1H); 3.72 (dd, J=11.5 and 7.5 Hz: 1H); 4.74 (mt:1H); 8.59 (broad s: 1H); 8.64 (broad s: 1H); 8.67 (broad s: 1H); 9.29(unresolved complex: 1H); 9.77 (unresolved complex: 1H); 10.16 (broad s:1H)].

N-(tert-Butyl)-N′-[(1RS)-1-hydroxymethyl-2-(2-pyrazinyl)ethyl]thiourea:11.2 cm³ of triethylamine are added with stirring to a solution of 7.91g of (2RS)-2-amino-3-(2-pyrazinyl)-1-propanol dihydrochloride in 80 cm³of ethanol, followed by addition of 7.2 cm³ of tert-butylisothiocyanate. The mixture is heated at a temperature in the region of50° C. for 18 hours. After cooling, the reaction medium is concentratedunder reduced pressure (1 kPa) at a temperature in the region of 40° C.,taken up in 100 cm³ of water and extracted with dichloromethane. Theorganic phases are combined, washed with 50 cm³ of water, dried overmagnesium sulfate, filtered and then concentrated under reduced pressure(1 kPa) at a temperature in the region of 40° C. 7.2 g ofN-(tert-butyl)-N′-[(1RS)-1-hydroxymethyl-2-(2-pyrazinyl)-ethyl]thioureaare obtained in the form of a colorless paste [mass spectrum: DCIm/z=269 MH⁺].

(2RS)-2-Amino-3-(2-pyrazinyl)-1-propanol dihydrochloride: A solution of11 g of N-[(1RS)-1-hydroxymethyl-2-(2-pyrazinyl)ethyl]acetamide in 30cm³ of 5N hydrochloric acid is heated at a temperature in the region of115° C. for 18 hours. The reaction mixture is concentrated under reducedpressure (1 kPa) at a temperature in the region of 40° C. 7.9 g of(2RS)-2-amino-3-(2-pyrazinyl)-1-propanol dihydrochloride are obtained inthe form of a black paste [mass spectrum: DCI m/z=154 MH⁺]

N-[(1RS)-1-Hydroxymethyl-2-(2-pyrazinyl)-ethyl]acetamide: 2.8 g ofsodium borohydride are added to a solution of 8.5 g of ethyl(2RS)-2-acetylamino-3-(2-pyrazinyl)propanoate in 100 cm³ of ethanol andthe mixture is then stirred at a temperature in the region of 20° C.After 18 hours, the reaction medium is taken up in 50 cm³ of water and100 cm³ of dichloromethane and the aqueous phase is concentrated underreduced pressure (1 kPa) at a temperature in the region of 40° C. 11 gof N-[(1RS)-1-hydroxymethyl-2-(2-pyrazinyl)-ethyl]acetamide are obtainedin the form of a brown paste [¹H NMR spectrum (300 MHz, (CD₃)₂SO-d₆ withaddition of a few drops of CD₃COOD-d₄ δ in ppm): 1.71 (s: 3H); 2.81 (dd,J=14.5 and 9 Hz: 1H); 3.03 (dd, J=14.5 and 5 Hz: 1H); 3.35 (dd, J=11 and6 Hz); 3.42 (dd, J=11 and 5 Hz: 1H); 4.11 (mt: 1H); 7.75 (residual d,J=8.5 Hz: 0.5H); 8.45 (d, J=2.5 Hz: 1H); 8.50 (broad s: 1H); 8.53 (mt:1H)]).

Ethyl (2RS)-2-acetylamino-3-(2-pyrazinyl)-propanoate: 12 cm³ of 6Nsodium hydroxide are added dropwise to a solution of 14 g of diethyl2-acetylamino-2-(2-pyrazinylmethyl)malonate in 240 cm³ of ethanol andthe mixture is then stirred at a temperature in the region of 20° C.After 1 hour, the reaction medium is neutralized with 6 cm³ of 12Nhydrochloric acid. After stirring for 2 hours at a temperature in theregion of 20° C., the reaction medium is filtered and the filtrates arethen concentrated under reduced pressure (1 kPa) at a temperature in theregion of 40° C. The residue is taken up in 200 cm³ of dioxane, refluxedfor 2 hours and concentrated as above. 8.5 g of ethyl(2RS)-2-acetylamino-3-(2-pyrazinyl)propanoate are obtained in the formof a cream-colored solid [¹H NMR spectrum (300 MHz, (CD₃)₂SO-d₆ δ inppm): 1.13 (t, J=7 Hz: 3H); 1.80 (s: 3H); 3.12 (dd, J=14 and 8.5 Hz:1H); 3.22 (dd, J=14 and 6 Hz: 1H); 4.07 (q, J=7 Hz: 2H); 4.71 (mt: 1H);8.36 (d, J=8 Hz: 1H); 8.52 (d, J=2.5 Hz: 1H); from 8.55 to 8.65 (mt:2H]).

Diethyl 2-acetylamino-2-(2-pyrazinylmethyl)-malonate may be preparedaccording to C. Petermann and J. L. Fauchere; Helv.Chim.Acta (1983),66(5), 1513-1518.

EXAMPLES 24 AND 25 4-(1-Imidazolylmethyl)-4,5-dihydro-2-thiazolylamine,enantiomer A, and 4-(1-imidazolylmethyl)-4,5-dihydro-2-thiazolylamine,enantiomer B

A racemic mixture of 0.75 g of(4RS)-4-(1-imidazolylmethyl)-4,5-dihydroxy-2-thiazolylamine is separatedon a Chiralcel OD10μ column in a heptane/2-isopropanol/triethylaminemixture (80/20/0.1 by volume). The fractions containing the expectedproduct are combined and then concentrated under reduced pressure (1kPa) at a temperature in the region of 40° C. to give 0.215 g of4-(1-imidazolyl-methyl)-4,5-dihydro-2-thiazolylamine, enantiomer A and0.21 g of 4-(1-imidazolylmethyl)-4,5-dihydro-2-thiazolylamine,enantiomer B.

4-(1-Imidazolylmethyl)-4,5-dihydro-2-thiazolylamine, enantiomer A: ¹HNMR spectrum (300 MHz, CD₃)₂SO-d₆, δ in ppm): 2.93 (dd, J=11 and 7 Hz:1H); 3.25 (dd, J=11 and 7 Hz: 1H); 4.03 (d, J=6 Hz: 2H); 4.38 (mt: 1H);6.49 (unresolved complex: 2H); 6.88 (broad s: 1H); 7.20 (broad s: 1H);7.64 (broad s: 1H).

4-(1-Imidazolylmethyl)-4,5-dihydro-2-thiazolylamine, enantiomer B: ¹HNMR spectrum (300 MHz, CD₃)₂SO-d₆, δ in ppm): 2.96 (dd, J=11 and 7.5 Hz:1H); from 3.20 to 3.40 (mt: 1H); 4.05 (d, J=6 Hz: 2H); 4.41 (mt: 1H);6.88 (broad s: 1H); 7.20 (broad s: 1H); 7.64 (broad s: 1H).

(4RS)-4-(1-Imidazolylmethyl)-4,5-dihydro-2-thiazolylamine: 5 cm³ of 4Nhydrochloric acid in dioxane are added to a solution of 1.39 g oftert-butylN-[(4RS)-4-(1-imidazolylmethyl)-4,5-dihydro-2-thiazolyl]carbamate in 5cm³ of dioxane, followed by addition of methanol to dissolve thereaction medium. After stirring at a temperature in the region of 20° C.for 48 hours, the reaction medium is concentrated under reduced pressure(1 kPa) at a temperature in the region of 40° C. and washed withisopropyl ether, with ethyl acetate and then with methanol. Thesuspension obtained is filtered and the filtrate is evaporated as aboveand then chromatographed on a column of silica gel, eluting with amixture of dichloromethane/methanol/28% aqueous ammonia (50/5/1 byvolume). The fractions containing the expected product are combined andthen concentrated under the above conditions to give 0.33 g of(4RS)-4-(1-imidazolylmethyl)-4,5-dihydro-2-thiazolyl-amine in the formof a viscous yellow oil [¹H NMR spectrum (300 MHz, CD₃)₂SO-d₆, δ inppm): 2.93 (mt: 1H); 3.26 (mt: 1H); 4.03 (d, J=6 Hz: 2H); 4.39 (mt: 1H);6.49 (unresolved complex: 2H); 6.87 (mt: 1H); 7.20 (mt: 1H); 7.63 (broads: 1H)].

Tert-ButylN-[(4RS)-4-(1-imidazolylmethyl)-4,5-dihydro-2-thiazolyl]carbamate: 0.21g of imidazole predissolved in 10 cm³ of dimethylformamide is added to asolution of 0.085 g of sodium hydride in 20 cm³ of dimethylformamide.After the sodium hydride has disappeared, a solution of 1 g oftert-butylN-[(4RS)-4-(p-toluenesulfonyloxymethyl)-4,5-dihydro-2-thiazolyl]carbamatein 10 cm³ of dimethylformamide is added and the mixture is then stirredat a temperature in the region of 70° C. for 3 hours. The reactionmedium is diluted with ethyl acetate, washed with water, dried overmagnesium sulfate and then concentrated under reduced pressure (1 kPa)at a temperature in the region of 40° C. The residue obtained ischromatographed on a column of alumina, eluting with ethyl acetate and amixture of ethyl acetate/methanol (80/20 by volume). The fractionscontaining the expected product are combined and then concentrated underthe above conditions to give 0.25 g of tert-butylN-[(4RS)-4-(1-imidazolylmethyl)-4,5-dihydro-2-thiazolyl]carbamate in theform of a sticky yellow mass [mass spectrum: DCI m/z=283 MH⁺ m/z=183(M-C₅H₇O₂)⁺].

Tert-ButylN-[(4RS)-4-(p-toluenesulfonyloxy-methyl)-4,5-dihydro-2-thiazolyl]carbamate:A solution of 0.8 g of tert-butylN-[(4RS)-4-hydroxymethyl-4,5-dihydro-2-thiazolyl]carbamate, 0.76 g ofp-toluenesulfonyl chloride and 0.56 cm³ of triethylamine in 25 cm³ ofdichloromethane is stirred for 16 hours at a temperature in the regionof 20° C. The solution obtained is concentrated under reduced pressure(1 kPa) at a temperature in the region of 40° C. The evaporation residueobtained is purified by chromatography at atmospheric pressure on acolumn of silica gel (particle size 60-200μ; diameter 2 cm; height 25 cm), eluting with a mixture of cyclohexane/ethyl acetate (70/30 by volume)and collecting 30 cm³ fractions. The fractions containing the expectedproduct are combined and then concentrated under the above conditions.0.8 g of tert-butylN-[(4RS)-4-(p-toluenesulfonyloxymethyl)-4,5-dihydro-2-thiazolyl]carbamateis obtained in the form of a white solid [¹H NMR spectrum (300 MHz,CD₃l₂, δ in ppm): 1.48 (s: 9H); 2.46 (s: 3H); 3.10 (dd, J=11.5 and 5.5Hz: 1H); 3.33 (dd, J=11.5 and 8.5 Hz: 1H); 3.97 (dd, J=9.5 and 8 Hz:1H); 4.06 (dd, J=9.5 and 4.5 Hz: 1H); 4.43 (mt: 1H); 7.36 (d, J=8 Hz:2H); 7.80 (d, J=8 Hz: 2H); from 8.50 to 9.40 (very broad unresolvedcomplex: 1H)].

Tert-Butyl N-[(4RS)-4-hydroxymethyl-4,5-dihydro-2-thiazolyl]carbamate:10 cm³ of aqueous 1N sodium hydroxide are added to a solution of 2 g oftert-butyl2-[(tert-butoxycarbonyl)imino]-(4RS)-4-[(tert-butoxycarbonyl)oxy]methyl-1,3-thiazolidine-3-carboxylatein 20 cm³ of methanol and the mixture is then stirred at a temperaturein the region of 20° C. for 4 hours. The reaction mixture isconcentrated under reduced pressure (1 kPa) at a temperature in theregion of 50° C. The residue obtained is taken up in 30 cm³ of water,filtered and washed with ethyl acetate and then with water. 0.37 g oftert-butyl N-[(4RS)-4-hydroxymethyl-4,5-dihydro-2-thiazolyl]-carbamateis obtained in the form of a white solid [mass spectrum: DCI m/z=233 MH⁺m/z=177 (M-C₄H₇)⁺].

Tert-Butyl2-[(tert-butoxycarbonyl)imino]-(4RS)-4-[(tert-butoxycarbonyl)oxy]methyl-1,3-thiazolidine-3-carboxylate:10.91 g of di-tert-butyl dicarbonate and 2.81 cm³ of triethylamine areadded to a solution of 1.98 g of(4RS)-4-hydroxymethyl-4,5-dihydro-2-thiazolylamine in 20 cm³ ofdichloromethane, and the mixture is then stirred at a temperature in theregion of 20° C. After 4 hours, a further 3 cm³ of triethylamine areadded and the mixture is then stirred for 16 hours at a temperature inthe region of 20° C. 50 cm³ of water are added to the reaction mixtureand the phases are separated after settling has taken place. The organicphase is dried over magnesium sulfate, filtered and concentrated underreduced pressure (1 kPa) at a temperature in the region of 40° C. 7 g oftert-butyl2-[(tert-butoxy-carbonyl)imino]-(4RS)-4-[(tert-butoxycarbonyl)oxy]-methyl-1,3-thiazolidine-3-carboxylateare obtained in the form of a white solid [mass spectrum: DCI m/z=433MH⁺ m/z=333 (M-C₅H₇O₂)⁺].

(4RS)-4-Hydroxymethyl-4,5-dihydro-2-thiazolylamine: A solution of 90 gof 1-tert-butyl-3-(2-hydroxy-1-hydroxymethylethyl)thiourea in 500 cm³ of6N hydrochloric acid is stirred at a temperature in the region of 100°C. After 3 hours, the reaction mixture is cooled to a temperature in theregion of 20° C. and is then concentrated under reduced pressure (1 kPa)at a temperature in the region of 50° C. The residue obtained is takenup in 100 cm³ of water, basified with 100 cm³ of 5N sodium hydroxide andthen concentrated as above. The oil obtained is stirred for 20 hours ata temperature in the region of 20° C. in 300 cm³ of ethanol, filteredand washed with 5 times 50 cm³ of ethanol and 3 times 100 cm³ ofmethanol. The various filtrates are combined, evaporated under reducedpressure (1 kPa) at a temperature in the region of 40° C. and thencrystallized from 400 cm³ of ethanol to give 31 g of(4RS)-4-hydroxymethyl-4,5-dihydro-2-thiazolylamine in the form of awhite solid melting at 122° C. [infrared spectrum (KBr): 3311; 3164;1648; 1601; 1349; 1051 and 982 cm⁻¹].

1-tert-Butyl-3-(2-hydroxy-1-hydroxymethyl-ethyl)thiourea: 30.4 cm³ oftert-butyl isothiocyanate are added to a solution of 14.6 g of2-amino-1,3-propanediol in 245 cm³ of ethanol, and the mixture is thenstirred at a temperature in the region of 20° C. for 94 hours. Thereaction medium is concentrated under reduced pressure (5 kPa) at atemperature in the region of 40° C. and the residue is slurried in amixture of 160 cm³ of petroleum ether and 26 cm³ of ethanol, and theproduct is filtered off and then dried in a desiccator under reducedpressure (0.1 kPa) at a temperature in the region of 60° C. 30 g of1-tert-butyl-3-(2-hydroxy-1-hydroxymethylethyl)thiourea are obtained inthe form of a white solid [¹H NMR spectrum (250 MHz, (CD₃)₂SO-d₆, δ inppm): 1.42 (s: 9H); 3.38 (mt: 2H); 3.54 (mt: 2H); 4.17 (unresolvedcomplex: 1H); 4.70 (t, J=5 Hz: 2H); 7.08 (d, J=8 Hz: 1H); 7.38 (s: 1H]).

EXAMPLE 26 (+)-(4R)-4-(4-Thiazolylmethyl)-4,5-dihydro-2-thiazolyl-aminedihydrochloride

A solution of 1.75 g ofN-(tert-butyl)-N′-[(1R)-1-hydroxymethyl-2-(4-thiazolyl)ethyl]thiourea in20 cm³ of 6N hydrochloric acid is heated at a temperature in the regionof 110° C. for 20 hours. The reaction medium is concentrated underreduced pressure (1 kPa) at a temperature in the region of 60° C., takenup in 5 cm³ of ethanol and then concentrated under the same conditionsas above. The residue is taken up in 5 cm³ of ethanol and the product isthen filtered off and dried in a desiccator under reduced pressure (0.1kPa) at a temperature in the region of 40° C. 0.54 g of(+)-(4R)-4-(4-thiazolylmethyl)-4,5-dihydro-2-thiazolylaminedihydrochloride is obtained in the form of a cream-colored solid meltingat 195° C. [¹H NMR spectrum (300 MHz, (CD₃)₂SO-d₆, δ in ppm): 3.67 (mt:2H); 3.41 (dd, J=11.5 and 5.5 Hz: 1H); 3.68 (dd, J=11.5 and 8 Hz: 1H);4.63 (mt: 1H); 7.59 (d, J=2 Hz: 1H); 9.14 (d, J=2 Hz: 1H); 9.18(unresolved complex: 1H); 9.66 (unresolved complex: 1H); 10.04 (broad s:1H); (α_(D) ²⁰=+24.2+/−0.8 at a concentration of 0.5% in methanol)].

N-(tert-Butyl)-N′-[(1R)-1-hydroxymethyl-2-(4-thiazolyl)ethyl]thiourea: Asolution of 2.5 g of tert-butylN-[(1R)-1-hydroxymethyl-2-(4-thiazolyl)-ethyl]carbamate in 20 cm3 of 6Nhydrochloric acid and 20 cm³ of dioxane is stirred at a temperature inthe region of 20° C. for 18 hours. The reaction mixture is concentratedunder reduced pressure (1 kPa) at a temperature in the region of 40° C.1.9 g of a white solid are obtained. The solid obtained is taken up in 6cm³ of absolute ethanol and 2 cm³ of triethylamine are added, followedby addition of 2.1 cm³ of tert-butyl isothiocyanate. The mixture isstirred at a temperature in the region of 50° C. for 20 hours. Thereaction medium is concentrated under reduced pressure (1 kPa) at atemperature in the region of 40° C. The residue is taken up in water andthe aqueous phase is extracted with dichloromethane. The organic phaseis dried over magnesium sulfate, filtered and concentrated under theabove conditions. The residue is dried in a desiccator under reducedpressure (0.1 kPa) at a temperature in the region of 40° C. 1.75 g ofN-(tert-butyl)-N′-[(1R)-1-hydroxymethyl-2-(4-thiazolyl)ethyl]thioureaare obtained in the form of a yellow solid [¹H NMR spectrum (300 MHz,(CD₃)₂SO-d₆, δ in ppm): 1.41 (s: 9H); 2.96 (dd, J=15 and 7 Hz: 1H); 3.05(dd, J=15 and 7 Hz: 1H); 3.41 (mt: 2H); 4.62 (unresolved complex: 1H);4.85 (t, J 5 Hz: 1H); 7.21 (d, J=8.5 Hz: 1H); 7.23 (broad s: 1H); 7.37(d, J 2 Hz: 1H); 9.04 (d, J=2 Hz: 1H)].

Tert-Butyl N-[(1R)-1-hydroxymethyl-2-(4-thiazolyl)ethyl]carbamate: 1.59cm³ of triethylamine are added with stirring to a solution of 3 g ofBOC-D-(4-thiazolyl)alanine in 50 cm³ of tetrahydrofuran. The reactionmedium is cooled to a temperature in the region of −18° C., followed byaddition, with stirring and under an inert atmosphere, of 1.16 cm³ ofisobutyl chloroformate. After stirring for 40 minutes at a temperaturein the region of −15° C., the reaction medium is rapidly filtered undercold conditions and a solution of 0.85 g of sodium borohydridepredissolved in 6 cm³ of water is then added to the filtrates, at atemperature in the region of −15° C. and with stirring. After stirringfor 18 hours at a temperature in the region of 20° C., the reactionmedium is diluted with 100 cm³ of water and extracted with ethylacetate. The organic phase is washed with water, dried over magnesiumsulfate, filtered and concentrated under reduced pressure (1 kPa) at atemperature in the region of 50° C. 2.5 g of tert-butylN-[(1R)-1-hydroxymethyl-2-(4-thiazolyl)ethyl]carbamate are obtained inthe form of a colorless oil [infrared spectrum (CCl₄): 3442, 3368, 2980,2932, 2874, 1710, 1501, 1392, 1367, 1243, 1171, 1048 and 875 cm⁻¹].

EXAMPLE 27 (+)-(4R)-4-(3-Aminopropyl)-4,5-diydro-2-thiazolylaminedihydrochloride

A solution of 9.6 g of benzylN-[(4R)-4-(3-tert-butylthioureido)-5-hydroxypentyl]-carbamate in 50 cm³of 6N hydrochloric acid is heated at a temperature in the region of 110°C. for 18 hours. The reaction medium is concentrated under reducedpressure (1 kPa) at a temperature in the region of 40° C., taken upsuccessively in 30 cm³ of ethanol and 20 cm³ of isopropanol,concentrating under the same conditions as above between each washing.The solid obtained is taken up in ethanol and diethyl ether, filteredoff and dried in a desiccator under reduced pressure (0.1 kPa) at atemperature in the region of 40° C. to give 2.8 g of(+)-(4R)-4-(3-aminopropyl)-4,5-diydro-2-thiazolylamine dihydrochloridein the form of a white solid melting at 166° C. [¹H NMR spectrum (300MHz, (CD₃)₂SO-d₆, δ in ppm): from 1.55 to 1.85 (mt: 4H); 2.81 (mt: 2H);3.25 (dd, J=11 and 6 Hz: 1H); 3.69 (dd, J=11 and 8 Hz: 1H); 4.27 (mt:1H); 8.16 (unresolved complex: 3H); 9.50 (broad unresolved complex: 2H);from 9.50 to 10.60 (very broad unresolved complex: 1H); (α_(D)²⁰=+7.5+/−0.4 at a concentration of 0.5% in methanol)].

Benzyl N-[(4R)-4-(3-tert-butylthioureido)-5-hydroxypentyl]carbamate:2.24 g of lithium chloride are added with stirring to a solution of 16 gof ethyl(2R)-5-{[(benzyloxy)carbonyl]amino}-2-(3-tert-butyl-thioureido)pentanoatein 200 cm³ of ethanol and 100 cm³ of tetrahydrofuran. After stirring for15 minutes at a temperature in the region of 0° C., 2.24 g of sodiumborohydride are added. After stirring for 20 hours at a temperature inthe region of 20° C., a further 0.5 g of sodium borohydride is added.The reaction medium is filtered and the filtrates are concentrated underreduced pressure (1 kPa) at a temperature in the region of 40° C. Theresidue is chromatographed at atmospheric pressure on a column of silicagel (particle size 60-200μ; diameter 5.6 cm; height 40 cm), eluting witha mixture of dichloromethane/ethyl acetate (8/2 by volume) and a mixtureof dichloromethane/ethyl acetate (6/4 by volume). The fractionscontaining the expected product are combined and then concentrated underthe above conditions. 9.6 g of benzylN-[(4R)-4-(3-tert-butylthioureido)-5-hydroxypentyl]carbamate areobtained in the form of a yellow oil [¹H NMR spectrum (300 MHz,(CD₃)₂SO-d₆, δ in ppm): from 1.30 to 1.60 (mt: 4H); 1.42 (s: 9H); 3.00(mt: 2H); from 3.25 to 3.40 (mt: 1H); 3.45 (mt: 1H); 4.21 (unresolvedcomplex: 1H); 4.76 (unresolved complex: 1H); 5.02 (s: 2H); 7.09 (d,J=8.5 Hz: 1H); 7.17 (broad s: 1H); 7.27 (t, J 5.5 Hz: 1H); from 7.30 to7.45 (mt: 5H)].

Ethyl(2R)-5-{[(Benzyloxy)carbonyl]amino}-2-(3-tert-butylthioureido)pentanoate:7.5 cm³ of tert-butyl isothiocyanate are added to a solution of 13 g ofethyl (2R)-2-amino-5-[(benzyloxy)carbonyl]amino-pentanoate hydrochloridein 200 cm³ of ethanol, and the mixture is then stirred at a temperaturein the region of 20° C. After 48 hours, the reaction medium isconcentrated under reduced pressure (1 kPa) at a temperature in theregion of 40° C. to give 16 g of ethyl(2R)-5-{[(benzyloxy)carbonyl]amino}-2-(3-tert-butyl-thioureido)pentanoatein the form of a colorless oil [mass spectrum: EI m/z=409 M⁺ m/z=232(C₁₃H14NO₃)⁺ m/z=142 (232-PhCH)⁺ m/z=91 (C₇H₇)⁺].

Ethyl (2R)-2-amino-5-[(benzoyloxy)carbonyl]-aminopentanoatehydrochloride: A solution of 12.5 g of(2R)-2-amino-5-[(benzyloxy)carbonyl]aminopentanoic acid hydrochloride in200 cm³ of ethanol is cooled to a temperature in the region of −20° C.6.5 cm³ of thionyl chloride are added dropwise and the mixture is thenstirred at a temperature in the region of 20° C. for 18 hours. Thereaction medium is concentrated under reduced pressure (1 kPa) at atemperature in the region of 40° C. to give 13 g of ethyl(2R)-2-amino-5-[(benzoyloxy)carbonyl]aminopentanoate hydrochloride [massspectrum: DCI m/z=295 MH⁺].

(2R)-2-Amino-5-[(benzyloxy)carbonyl]amino-pentanoic acid hydrochloride:30 g of basic copper II carbonate are added to a solution of 15.5 g ofD-ornithine hydrochloride in 1 dm³ of water. The mixture is heated at atemperature in the region of 100° C. for 2 hours, filtered while hot andwashed with water. The filtrates are cooled to a temperature in theregion of 20° C., followed by addition of 14.5 g of magnesium oxide withstirring. The reaction medium is cooled to a temperature in the regionof 0° C., followed by addition of 4 times 15.5 cm³ of benzylchloroformate. After 18 hours at a temperature in the region of 20° C.,the mixture is filtered. The solid is washed successively with 3 times30 cm³ of water and 3 times 30 cm³ of diethyl ether and is thensuspended in 500 cm³ of 1N hydrochloric acid with a gentle stream ofhydrogen sulfide for 2 hours. The suspension is filtered and the solidis washed with 0.5N hydrochloric acid. The filtrates are brought to pH4-5 with dilute aqueous ammonia to give a white precipitate. Afterfiltration and drying in a desiccator, 12.5 g of(2R)-2-amino-5-[(benzyloxy)carbonyl]aminopentanoic acid hydrochlorideare obtained in the form of a white solid [¹H NMR spectrum (300 MHz,(CD₃)₂SO-d₆, δ in ppm): from 1.40 to 1.80 (mt: 4H); 2.99 (mt: 2H); 3.11(mt: 1H); 5.02 (broad s: 2H); from 7.25 to 7.45 (mt: 6H)].

EXAMPLE 28 (+)-(4R)-4-(4-Hydroxybenzyl)-4,5-dihydro-2-thiazolyl-aminehydrochloride

A solution of 0.2 g ofN-(tert-butyl)-N′-[(1R)-1-hydroxymethyl-2-(4-hydroxyphenyl)ethyl]-thioureain 2.6 cm³ of 6N hydrochloric acid is heated at a temperature in theregion of 110° C. for 18 hours. The reaction medium is concentratedunder reduced pressure (1 kPa) at a temperature in the region of 55° C.and is then taken up successively in 10 cm³ of isopropyl ether, 10 cm³of diethyl ether, 10 cm³ of pentane, 10 cm³ of petroleum ether and 10cm³ of isopropyl ether, concentrating under the same conditions as abovebetween each wash. The solid obtained is dried in a desiccator underreduced pressure (0.1 kPa) at a temperature in the region of 40° C. togive 0.098 g of(+)-(4R)-4-(4-hydroxybenzyl)-4,5-dihydro-2-thiazolyl-amine hydrochloridein the form of an orange-colored solid [¹H NMR spectrum (300 MHz,(CD₃)₂SO-d₆, δ in ppm): 2.78 (dd, J=13.5 and 7.5 Hz: 1H); 2.88 (dd,J=13.5 and 5.5 Hz: 1H); 3.26 (dd, J=11.5 and 6 Hz: 1H); 3.55 (dd, J=11.5and 7.5 Hz: 1H); 4.45 (mt: 1H); 6.74 (d, J=8.5 Hz: 2H); 7.07 (d, J=8.5Hz: 2H); 9.09 (unresolved complex: 1H); 9.41 (s: 1H); 9.56 (unresolvedcomplex: 1H); 9.97 (broad s: 1H); (α_(D) ²⁰=+9.5+/−0.5 at aconcentration of 0.5% in methanol)].

N-(tert-Butyl)-N′-[(1R)-1-hydroxymethyl-2-(4-hydroxyphenyl)ethyl]thiourea:0.15 cm³ of triethylamine is added to a solution of 0.2 g of4-[(2R)-2-amino-3-hydroxypropyl]phenol in 10 cm³ of absolute ethanol,followed by addition of 0.18 cm³ of tert-butyl isothiocyanate. Themixture is stirred at a temperature in the region of 20° C. for 18 hoursand is then heated at a temperature in the region of 60° C. for 4 hours.After cooling, the reaction medium is evaporated under reduced pressure(1 kPa) at a temperature in the region of 40° C. and thenchromatographed under an argon pressure of 60 kPa on a column of silicagel (particle size 40-63μ; diameter 2.5 cm; height 29 cm), eluting witha mixture of dichloromethane/methanol (98/2 by volume). The fractionscontaining the expected product are combined and then concentrated underthe above conditions. 0.2 g ofN-(tert-butyl)-N′-[(1R)-1-hydroxymethyl-2-(4-hydroxyphenyl)ethyl]thioureais obtained in the form of a colorless viscous oil [¹H NMR spectrum (300MHz, (CD₃)₂SO-d₆, δ in ppm): 1.42 (s: 9H); 2.63 (dd, J=13.5 and 8 Hz:1H); 2.72 (dd, J=13.5 and 5.5 Hz: 1H); from 3.25 to 3.40 (mt: 2H); 4.29(unresolved complex: 1H); 4.83 (t, J=4.5 Hz: 1H); 6.67 (d, J=8 Hz: 2H);7.05 (d, J=8 Hz: 2H); 7.15 (d, J=8 Hz: 1H); 7.26 (broad s: 1H); 9.16 (s:1H)].

4-[(2R)-2-Amino-3-hydroxypropyl)]phenol: A solution of 2.2 g oftert-butyl N-[(1R)-1-hydroxy-methyl-2-(4-hydroxyphenyl)ethyl]carbamatein 24 cm³ of dichloromethane and 4 cm³ of dioxane is added, withstirring and under an inert atmosphere, at a temperature in the regionof 20° C., to a solution of 20.5 cm³ of 4N hydrochloric acid in dioxane.The mixture is heated at a temperature in the region of 60° C. for 18hours and is then cooled and concentrated under reduced pressure (1 kPa)at a temperature in the region of 60° C. The residue is taken up in 50cm³ of dichloromethane, filtered, slurried in 20 cm³ of diethyl ether,filtered again, washed with twice 5 cm³ of diethyl ether and then driedin a desiccator under reduced pressure (0.1 kPa) at a temperature in theregion of 40° C. 1.4 g of 4-[(2R)-2-amino-3-hydroxy-propyl)]phenol areobtained in the form of a beige-colored solid melting at 156° C. [¹H NMRspectrum (300 MHz, (CD₃)₂SO-d₆, δ in ppm): 2.69 (dd, J=13 and 9 Hz: 1H);2.79 (dd, J=13 and 5.5 Hz: 1H); 3.23 (mt: 1H); from 3.30 to 3.45 (mt:1H); 3.51 (ddd, J=11.5−5 and 4.5 Hz: 1H); 5.32 (t, J=5 Hz: 1H); 6.73 (d,J=8.5 Hz: 2H); 7.06 (d, J=8.5 Hz: 2H); 7.95 (unresolved complex: 3H);9.37 (s: 1H)].

Tert-Butyl N-[(1R)-1-hydroxymethyl-2-(4-hydroxyphenyl)ethyl]carbamate: Asolution of 29.6 cm³ of lithium aluminum hydride at 1M intetrahydrofuran is added, with stirring and under an inert atmosphere,at a temperature in the region of 20° C., to a solution of 4.38 g ofmethyl BOC-D-tyrosinate in 25 cm³ of tetrahydrofuran. After addition of60 cm³ of tetrahydrofuran, the reaction mixture is heated at atemperature in the region of 70° C. for 3 hours. The reaction mixture iscooled and then concentrated under reduced pressure (1 kPa) at atemperature in the region of 60° C. The evaporation residue is dried ina desiccator under reduced pressure (0.1 kPa) at a temperature in theregion of 40° C. and is then chromatographed under an argon pressure of60 kPa on a column of silica gel (particle size 40-63μ; diameter 7 cm;height 24 cm), eluting with 10 dm³ of a dichloromethane/methanol mixture(98/2 by volume), 2 dm³ of a dichloromethane/methanol mixture (95/5 byvolume) and 2 dm³ of a dichloromethane/methanol mixture (90/10 byvolume). The fractions containing the expected product are combined andthen concentrated under the above conditions. 2.2 g of tert-butylN-[(1R)-1-hydroxymethyl-2-(4-hydroxyphenyl)ethyl]-carbamate are obtainedin the form of a white foam [¹H NMR spectrum (400 MHz, (CD₃)₂SO-d₆, δ inppm): 1.35 (s: 9H); 2.46 (dd, J=14 and 8 Hz: 1H); 2.68 (dd, J=14 and 6Hz: 1H); from 3.15 to 3.40 (mt: 2H); 3.50 (mt: 1H); 4.61 (mt: 1H); 6.48(d, J=8.5 Hz: 1H); 6.65 (d, J=8 Hz: 2H); 6.97 (d, J=8 Hz: 2H); 9.11(broad s: 1H)].

EXAMPLE 29 (+)-4-(4-Pyridylsulphanylmethyl)-4,5-dihydro-2-thiazolylamine

A racemic mixture of 1.75 g of(4RS)-4-(4-pyridylsulphanylmethyl)-4,5-dihydro-2-thiazolylaminedihydrochloride is separated on a Chiralcel OD 10μ column in aheptane/2-isopropanol/triethylamine mixture (80/20/0.1 by volume) togive 0.43 g of(+)-4-(4-pyridylsulphanylmethyl)-4,5-dihydro-2-thiazolylamine [¹H NMRspectrum (300 MHz, (CD₃)₂SO-d₆, δ in ppm): 3.12 (dd, J=11 and 6.5 Hz:1H); 3.20 (d, J=6.5 Hz: 2H); 3.44 (dd, J=11 and 7.5 Hz: 1H); 4.32 (mt:1H); 6.49 (unresolved complex: 2H); 7.30 (dd, J=5 and 1.5 Hz: 2H); 8.37(dd, J=5 and 1.5 Hz: 2H), (α_(D) ²⁰=+13.3+/−0.6 at a concentration of0.5% in methanol)].

(4RS)-4-(4-pyridylsulphanylmethyl)-4,5-dihydro-2-thiazolylaminedihydrochloride: 5 cm³ of 4N hydrochloric acid in dioxane are added to asolution of 0.356 g of tert-butylN-(4RS)-4-(4-pyridylsulphanyl-methyl)-4,5-dihydro-2-thiazolyl]carbamatein 5 cm³ of methanol and 20 cm³ of dioxane, and the mixture is thenstirred at a temperature in the region of 20° C. for 18 hours. Thereaction medium is concentrated under reduced pressure (5 kPa) at atemperature in the region of 40° C., taken up in diisopropyl ether andthen filtered to give 0.287 g of(4RS)-4-(4-pyridylsulphanylmethyl)-4,5-dihydro-2-thiazolylaminedihydrochloride in the form of a cream-colored solid [¹H NMR spectrum(300 MHz , (CD₃)₂SO-d₆, δ in ppm): 3.45 (dd, J=11 and 4.5 Hz: 1H); 3.61(dd, J=14 and 7 Hz: 1H); 3.69 (dd, J=14 and 5.5 Hz: 1H); 3.80 (dd, J=12and 8 Hz: 1H); 4.59 (mt: 1H); 8.00 (broad d, J=6.5 Hz: 2H); 8.66 (broadd, J=6.5 Hz: 2H); 9.60 (unresolved complex: 1H); 9.81 (unresolvedcomplex: 1H); from 10.00 to 10.50 (broad unresolved complex: 1H).

tert-ButylN-[(4RS)-4-(4-pyridylsulphanyl-methyl)-4,5-dihydro-2-thiazolyl]carbamate:a suspension of 1.5 g of tert-butylN-[(4RS)-4-(p-toluenesulfonyl-oxymethyl)-4,5-dihydro-2-thiazolyl]carbamatein 50 cm³ of acetonitrile is heated until the reagent has dissolved and0.604 g of 4-mercaptopyridine is then added with stirring. After coolingto a temperature in the region of 20° C., 1.07 g of potassium carbonateare added. After stirring for 48 hours at a temperature in the region of20° C., the reaction mixture is filtered. The filtrate is concentratedunder reduced pressure (1 kPa) at a temperature in the region of 50° C.The residue obtained is taken up in ethyl acetate and water and thephases are separated after settling has taken place. The organic phaseis washed with sodium chloride solution, dried over magnesium sulfateand chromatographed on a column of alumina, eluting with successivemixtures of ethyl acetate/cyclohexane (50/50 by volume). The fractionscontaining the expected product are purified by chromatography on acolumn of silica gel, eluting with ethyl acetate. The fractionscontaining the expected product are combined and then concentrated underthe above conditions. 0.356 g of tert-butylN-[(4RS)-4-(4-pyridylsulphanylmethyl)-4,5-dihydro-2-thiazolyl]carbamateis obtained in the form of a yellow oil [¹H NMR spectrum (300 MHz,(CD₃)₂SO-d₆, δ in ppm): 1.42 (s: 9H); 3.09 (dd, J=11.5 and 6 Hz: 1H);3.29 (mt: 2H); 3.40 (dd, J=11.5 and 8 Hz: 1H); 4.25 (mt: 1H); 7.35 (dd,J=5 and 1.5 Hz: 2H); 8.40 (dd, J=5 and 1.5 Hz: 2H); from 9.70 to 10.00(broad unresolved complex: 1H)].

EXAMPLE 30 (4R)-4-(1-Oxy-4-pyridylmethyl)-4,5-dihydro-2-thiazolylaminehydrochloride

A solution of 0.6 g ofN-(tert-butyl)-N′-[(1R)-1-hydroxymethyl-2-(1-oxy-4-pyridyl)ethyl]thioureain 6 cm³ of 6N hydrochloric acid is heated at a temperature in theregion of 110° C. for 18 hours. The reaction medium is concentratedunder reduced pressure (1 kPa) at a temperature in the region of 55° C.,taken up in twice 20 cm³ of ethanol, concentrated under the sameconditions as above, taken up in 10 cm³ of ethanol, filtered and driedin a desiccator under reduced pressure (0.1 kPa) at a temperature in theregion of 40° C. to give 0.296 g of(4R)-4-(1-oxy-4-pyridylmethyl)-4,5-dihydro-2-thiazolylaminehydrochloride in the form of cream-colored crystals [¹H NMR spectrum(300 MHz, (CD₃)₂SO-d₆, δ in ppm): 3.04 (limiting AB: 2H); 3.34 (dd, J=12and 5.5 Hz: 1H); 3.68 (dd, J=12 and 8 Hz: 1H); 4.63 (mt: 1H); 7.75 (d,J=7 Hz: 2H); 8.65 (d, J=7 Hz: 2H); 9.30 (unresolved complex: 1H); 9.79(unresolved complex: 1H); 10.30 (broad s: 1H)].

N-(tert-Butyl)-N′-[(1R)-1-hydroxymethyl-2-(1-oxy-4-pyridyl)ethyl]thiourea:2.6 cm³ of triethylamine are added to a solution of 1.5 g of(2R)-2-amino-3-(1-oxy-4-pyridyl)-1-propanol hydrochloride in 30 cm³ ofabsolute ethanol, followed by addition of 1.53 cm³ of tert-butylisothiocyanate. After adding 20 cm³ of methanol, the mixture is stirredat a temperature in the region of 20° C. for 18 hours and is thenconcentrated under reduced pressure (1 kPa) at a temperature in theregion of 40° C. 1 cm³ of triethylamine is added to the evaporationresidue taken up in 10 cm³ of methanol, followed by addition of 1.5 cm³of tert-butyl isothiocyanate. The mixture is stirred at a temperature inthe region of 20° C. for 48 hours. The reaction medium is concentratedunder reduced pressure (5 kPa) at a temperature in the region of 40° C.and the product is taken up in 25 cm³ of ethyl acetate, filtered off andwashed with 10 cm³ of ethyl acetate and 20 cm³ of isopropyl ether. Thetriethylamine hydrochloride is removed by passage through a column ofalumina. 0.6 g ofN-(tert-butyl)-N′-[(1R)-1-hydroxy-methyl-2-(1-oxy-4-pyridyl)ethyl]thioureais obtained in the form of white crystals [R^(f)=0.36 in adichloro-methane/methanol mixture (90/10 by volume) on a Merck 60 F₂₅₄alumina plate (type E)].

(2R)-2-Amino-3-(1-oxy-4-pyridyl)-1-propanol hydrochloride: a solution of20 cm³ of 4N hydrochloric acid in dioxane is added with stirring, at atemperature in the region of 20° C., to a solution of 2 g of tert-butylN-[(1R)-1-hydroxymethyl-2-(1-oxy-4-pyridyl)ethyl]carbamate in 20 cm³ ofdioxane. The mixture is stirred at a temperature in the region of 20° C.for 18 hours and is then taken up in 40 cm³ of dioxane, stirred for 30minutes and filtered. The precipitate is washed with 10 cm³ of dioxaneand then with 25 cm³ of isopropyl ether and dried in a desiccator underreduced pressure (0.1 kPa) at a temperature in the region of 40° C. 1.54g of (2R)-2-amino-3-(1-oxy-4-pyridyl)-1-propanol hydrochloride areobtained in the form of a pale yellow solid [¹H NMR spectrum (300 MHz,(CD₃)₂SO-d₆, δ in ppm): 3.08 (d, J=6 Hz: 2H); from 3.40 to 3.55 (mt:2H); from 3.55 to 3.70 (mt: 1H); 7.78 (d, J=6.5 Hz: 2H); 8.26 (broad s:3H); 8.71 (d, J=6.5 Hz: 2H)].

Tert-Butyl N-[(1R)-1-hydroxymethyl-2-(1-oxy-4-pyridyl)ethyl]carbamate: 1g of tert-butyl (1R)-1-(4-pyridylmethyl)-2-hydroxyethylcarbamate in 5cm³ of dichloromethane is added to a solution of 1.01 g of 77%m-chloroperbenzoic acid in 10 cm³ of dichloromethane, and the mixture isthen heated to a temperature in the region of 60° C. After 45 minutes, afurther 0.65 g of m-chloroperbenzoic acid is added and the mixture isheated for 1 hour at a temperature in the region of 60° C., and theabove operation is then repeated. After heating for 2 hours at atemperature in the region of 60° C., the reaction medium is cooled andthen taken up in 50 cm³ of dichloromethane and 50 cm³ of 1N sodiumhydroxide. The aqueous phase is concentrated under reduced pressure (1kPa) at a temperature in the region of 40° C., taken up in 50 cm³ ofdichloromethane, dried over magnesium sulfate, filtered and concentratedunder reduced pressure (1 kPa) at a temperature in the region of 40° C.0.15 g of tert-butylN-[(1R)-1-hydroxymethyl-2-(1-oxy-4-pyridyl)ethyl]carbamate is obtained[¹H NMR spectrum (300 MHz, (CD₃)₂SO-d₆, δ in ppm): 1.32 (s: 9H); from2.45 to 2.60 (mt: 1H); 2.86 (very broad d, J=13.5 Hz: 1H); from 3.20 to3.45 (mt: 2H); 3.63 (mt: 1H); 4.80 (mt: 1H); 6.67 (broad d, J=9 Hz: 1H);7.23 (broad d, J=5.5 Hz: 2H); 8.14 (broad d, J=5.5 Hz: 2H)].

EXAMPLE 31(+)-4-(1,2,4-Triazol-1-ylmethyl)-4,5-dihydro-2-thiazol-ylaminedihydrochloride

A racemic mixture of 0.35 g of(4RS)-4-(1,2,4-triazol-1-ylmethyl-4,5-dihydro-2-thiazolylaminedihydrochloride is separated on a Chiralpak AS 20μ column in aheptane/ethanol/triethylamine mixture (80/20/0.1 by volume). Thefractions containing the expected product are combined and thenconcentrated under reduced pressure (1 kPa) at a temperature in theregion of 40° C. to give 0.08 g of(+)-4-(1,2,4-triazol-1-ylmethyl)-4,5-dihydro-2-thiazolylaminedihydro-chloride in the form of a yellow solid [¹H NMR spectrum (300MHz, (CD₃)₂SO-d₆, δ in ppm): 3.46 (dd, J=11.5 and 4.5 Hz: 1H); 3.76 (dd,J=11.5 and 8.5 Hz: 1H); 4.51 (d, J=5 Hz: 2H); 4.69 (mt: 1H); 8.13 (broads: 1H); 8.68 (broad s: 1H); 9.30 (unresolved complex: 1H); 9.73(unresolved complex: 1H); 10.10 (broad s: 1H), (α_(D) ²⁰=+13.2+/−0.7 ata concentration of 0.5% in methanol)].

(4RS)-4-(1,2,4-Triazol-1-ylmethyl)-4,5-dihydro-2-thiazolylaminedihydrochloride: a solution of 0.3 g of tert-butylN-[(4RS)-4-(1,2,4-triazol-1-yl-methyl)-4,5-dihydro-2-thiazolyl]carbamatein 10 cm³ of 4N hydrochloric acid in dioxane is stirred at a temperaturein the region of 20° C. for 34 hours. The reaction medium is filteredand then washed with 3 times 5 cm³ of diethyl ether and dried in adesiccator. 0.14 g of(4RS)-4-(1,2,4-triazol-1-ylmethyl)-4,5-dihydro-2-thiazolylaminedihydrochloride is obtained in the form of a white foam [mass spectrum:EI m/z=184 MH⁺ m/z=183 M⁺ m/z=114 C₄H₆N₂ ⁺M/z=101 C₃H₅N₂S⁺ base peakm/z=36 HCl DCI m/z=184 MH⁺].

Tert-ButylN-[(4RS)-4-(1,2,4-triazol-1-yl-methyl)-4,5-dihydro-2-thiazolyl]carbamate:0.6 g of 1,2,4-triazole is added, at a temperature in the region of 20°C. and under an inert atmosphere, to a solution of 0.35 g of sodiumhydride in 7 cm³ of dimethyl sulfoxide. The mixture is stirred at atemperature in the region of 20° C. for 45 minutes, followed by additionof 1 g of tert-butylN-[(4RS)-4-(iodomethyl)-4,5-dihydro-2-thiazolyl]carbamate. Afterstirring for 3 hours at a temperature in the region of 60° C., 30 cm³ ofsaturated ammonium chloride solution are added to the reaction mediumand the resulting mixture is extracted with 4 times 10 cm³ of ethylacetate. The organic phases are washed with 10 cm³ of saturated sodiumchloride solution, dried over magnesium sulfate, filtered and thenconcentrated under reduced pressure (1 kPa) at a temperature in theregion of 40° C. The residue is chromatographed under an argon pressureof 70 kPa on a column of silica gel (particle size 40-63μ; diameter 4cm; height 18 cm), eluting with a dichloromethane/methanol mixture (5/1by volume). The fractions containing the expected product are combinedand then concentrated under the above conditions. 0.34 g of tert-butylN-[(4RS)-4-(1,2,4-triazol-1-ylmethyl)-4,5-dihydro-2-thiazolyl]carbamateis obtained in the form of a white foam [mass spectrum: EI m/z=283 M⁺.m/z=201 C₈H₁₃N₂O₂S⁺ m/z=145 C₄H₅N₂O₂S⁺ m/z=101 C₃H₅N₂S⁺ m/z=82 C₃H₄N₃ ⁺m/z=57 C₄H₉ ⁺].

Tert-Butyl N-[(4RS)-4-(iodomethyl)-4,5-dihydro-2-thiazolyl]carbamate: 17g of sodium bicarbonate are added, at a temperature in the region of 20°C., to a suspension of 25.4 g of tert-butylallylsulfanyl-[(tert-butoxycarbonyl)amino]methylidene-carbamate in 650cm³ of dichloromethane, followed by addition of a solution of 24.4 g ofiodine predissolved in 850 cm³ of dichloromethane. After 72 hours at atemperature in the region of 20° C., 500 cm³ of water and 500 cm³ ofsaturated sodium bicarbonate solution are added to the reaction mediumand the resulting mixture is then extracted with twice 1 dm³ of ethylacetate. The organic phases are washed with saturated sodium sulfitesolution and then with saturated sodium chloride solution, dried overmagnesium sulfate, filtered and then concentrated under reduced pressure(1 kPa) at a temperature in the region of 50° C. The residue obtained iscrystallized from ethyl acetate. 20.5 g of tert-butylN-[(4RS)-4-(iodomethyl)-4,5-dihydro-2-thiazolyl]carbamate are obtainedin the form of a yellow solid [¹H NMR spectrum (300 MHz, (CD₃)₂SO-d₆, δin ppm): 1.41 (s: 9H); 2.97 (dd, J=11.5 and 7 Hz: 1H); from 3.30 to 3.50(mt: 3H); 4.12 (mt: 1H); 9.89 (unresolved complex: 1H)].

Tert-Butylallylsulfanyl-[(tert-butoxycarbonyl)amino]methylidenecarbamate: acatalytic amount of 4-(dimethylamino)pyridine and 4.7 cm³ oftriethylamine are added to a solution of 5 g of 2-allylisothioureahydrochloride in 50 cm³ of dichloromethane, followed by dropwiseaddition of a solution of 7.1 g of di-tert-butyl dicarbonatepredissolved in 30 cm³ of dichloromethane. After 48 hours, the reactionmedium is concentrated under reduced pressure (1 kPa) at a temperaturein the region of 40° C. The residue is chromatographed under an argonpressure of 70 kPa, on a column of silica gel (particle size 40-63μ;diameter 4 cm; height about 30 cm), eluting with an ethylacetate/cyclohexane mixture (90/10 by volume). The fractions containingthe expected product are combined and then concentrated under the aboveconditions. 0.2 g of tert-butylallylsulfanyl-[(tert-butoxycarbonyl)amino]methylidene-carbamate isobtained [mass spectrum: DCI m/z=317 MH⁺ m/z=261 C₁₀H₁₇O₄N₂S⁺ m/z=217C₉H₁₇O₂N₂S⁺ m/z=161 C₅H₉O₂N₂S⁺].

2-Allylisothiorurea hydrochloride: 16 cm³ of allyl chloride are added,at a temperature in the region of 20° C., to a suspension of 15 g ofthiourea in 120 cm³ of ethanol. After 15 hours at a temperature in theregion of 80° C., the reaction medium is concentrated under reducedpressure (1 kPa) at a temperature in the region of 50° C. The solidobtained is taken up in 3 times 100 cm³ of diethyl ether and thenfiltered. 29 g of 2-allylisothiourea hydrochloride are obtained in theform of a white solid [mass spectrum: DCI m/z=117 MH⁺].

EXAMPLE 32(+)-(4R,5R)-5-(Ethyl-4-(4-pyridylmethyl)-4,5-dihydro-2-thiazolylamine

A suspension of 4.2 g ofN-tert-butyl-N′-[(1R,2S)-1-(4-pyridylmethyl)-2-hydroxybutyl]thiourea in40 cm³ of 6N hydrochloric acid is heated at a temperature in the regionof 100° C. for 20 hours. After cooling to room temperature, the reactionmixture is concentrated under reduced pressure (1 kPa) at a temperaturein the region of 50° C. The residue is chromatographed at atmosphericpressure on a column of silica gel (particle size 40-63μ; diameter 3.6cm; height 24 cm), eluting with a dichloromethane/methanol mixture (98/2by volume) and then with a dichloro-methane/methanol mixture (97/3 byvolume). The fractions containing the expected product are combined andthen concentrated under the above conditions, taken up in 30 cm³ ofdichloromethane and basified with 1N sodium hydroxide. The organic phaseis dried over magnesium sulfate, filtered and dried in a desiccatorunder reduced pressure (0.1 kPa) at a temperature in the region of 40°C. 1.4 g of(+)-(4R,5R)-5-(ethyl-4-(4-pyridylmethyl)-4,5-dihydro-2-thiazolylamineare obtained in the form of a white solid melting at 124° C. [¹H NMRspectrum (300 MHz, (CD₃)₂SO-d₆, δ in ppm): 0.83 (t, J=7.5 Hz: 3H); 1.43(mt: 1H); 1.61 (mt: 1H); 2.70 (limiting AB: 2H); 3.40 (mt: 1H); 4.08(mt: 1H); 6.28 (unresolved complex: 2H); 7.29 (broad d, J=5.5 Hz: 2H);8.45 (broad d, J=5.5 Hz: 2H), (α_(D) ²⁰=+166.9+/−2.4 at a concentrationof 0.5% in methanol)].

N-tert-Butyl-N′-[(1R,2S)-1-(4-pyridylmethyl)-2-hydroxybutyl]thiourea:4.3 cm³ of triethylamine are added to a solution of 3.6 g of(2R,3S)-2-amino-1-(4-pyridyl)-3-pentanol dihydrochloride in 60 cm³ ofethanol, followed by addition of 2.6 cm³ of tert-butyl isothiocyanate.The mixture is heated at a temperature in the region of 50° C. for 18hours. After cooling, the reaction medium is concentrated under reducedpressure (1 kPa) at a temperature in the region of 40° C. and theresidue is taken up in 50 cm³ of water and 100 cm³ of dichloromethane.The organic phase is washed with 30 cm³ of water, dried over sodiumsulfate, filtered and concentrated under the above conditions. 4.3 g ofN-tert-butyl-N′-[(1R,2S)-1-(4-pyridylmethyl)-2-hydroxybutyl]thiourea areobtained in the form of a thick colorless oil [¹H NMR spectrum (300 MHz,(CD₃)₂SO-d₆, δ in ppm): 0.80 (t, J=7.5 Hz: 3H); from 1.25 to 1.55 (mt:2H); 1.37 (s: 9H); 2.72 (dd, J=14 and 9 Hz: 1H); 2.93 (dd, J=14 and 4.5Hz: 1H); 3.37 (mt: 1H); 4.60 (mt: 1H); 4.88 (unresolved complex: 1H);7.11 (s: 1H); 7.16 (d, J=8.5 Hz: 1H); 7.26 (broad d, J=5.5 Hz: 2H); 8.43(broad d, J=5.5 Hz: 2H)].

(2R,3S)-2-Amino-1-(4-pyridyl)-3-pentanol dihydrochloride: a solution of50 cm³ of 4N hydrochloric acid in dioxane is added, with stirring and ata temperature in the region of 20° C., to a solution of 4 g oftert-butyl N-[(1R,2S)-2-hydroxy-1-(4-pyridylmethyl)-butyl]carbamate in50 cm³ of dioxane. The mixture is stirred at a temperature in the regionof 20° C. for 18 hours and is then concentrated under reduced pressure(1 kPa) at a temperature in the region of 60° C. 3.6 g of(2R,3S)-2-amino-1-(4-pyridyl)-3-pentanol dihydrochloride are obtained inthe form of a white solid [¹H NMR spectrum (300 MHz, (CD₃)₂SO-d₆, δ inppm): 0.92 (t, J=7.5 Hz: 3H); from 1.30 to 1.65 (mt: 2H); 3.13 (dd, J=14and 9 Hz: 1H); 3.28 (dd, J=14 and 5 Hz: 1H); 3.52 (mt: 1H); 3.68 (mt:1H); 8.11 (broad d, J=6.5 Hz: 2H); 8.25 (unresolved complex: 3H); 8.90(broad d, J=6.5 Hz: 2H)].

Tert-Butyl N-[(1R,2S)-2-hydroxy-1-(4-pyridylmethyl)butyl]carbamate: 9.5g of an 85%/15% mixture of the two diastereoisomers of tert-butylN-[(2RS)-2-hydroxy-(1R)-1-(4-pyridylmethyl)butyl]carbamate is separatedon a Kromasil® 10μ C8 column in anacetonitrile/methanol/tetrahydrofuran/water mixture (15/15/5/65 byvolume). The fractions containing the expected product are concentratedunder reduced pressure (1 kPa) at a temperature in the region of 40° C.to give 4 g of tert-butylN-[(1R,2S)-2-hydroxy-1-(4-pyridylmethyl)butyl]carbamate dihydrochloridein the form of a white solid [¹H NMR spectrum (300 MHz, (CD₃)₂SO-d₆, δin ppm): 0.91 (t, J=7.5 Hz: 3H); 1.26 (s: 9H); 1.30 (mt: 1H); 1.52 (mt:1H); from 2.45 to 2.60 (mt: 1H); 3.02 (dd, J=14 and 3.5 Hz: 1H); 3.28(mt: 1H); 3.53 (mt: 1H); 4.71 (d, J=6 Hz: 1H); 6.62 (d, J=9.5 Hz: 1H);7.20 (broad d, J=5.5 Hz: 2H); 8.42 (broad d, J=5.5 Hz: 2H)].

Tert-Butyl N-[(2RS)-2-hydroxy-(1R)-1-(4-pyridylmethyl)butyl]carbamate:2.1 g of sodium borohydride are added, with stirring and at atemperature in the region of 10° C., to a solution of 10.5 g oftert-butyl N-[(1R)-2-oxobutyl-1-(4-pyridyl-methyl)]carbamate in 150 cm³of ethanol, and the mixture is then stirred at a temperature in theregion of 20° C. for 18 hours. The reaction medium is concentrated underreduced pressure (1 kPa) at a temperature in the region of 40° C., takenup in 100 cm³ of water and extracted with 200 cm³ of ethyl acetate. Theorganic phase is dried over magnesium sulfate, filtered and concentratedunder reduced pressure (1 kPa) at a temperature in the region of 40° C.9.5 g of an 85%/15% mixture of the two diastereoisomers of tert-butylN-[(2RS)-2-hydroxy-(1R)-1-(4-pyridylmethyl)butyl]carbamate are obtainedin the form of a yellow gum [¹H NMR spectrum (300 MHz, (CD₃)₂SO-d₆, δ inppm). We observe a mixture of two diastereoisomers in proportions of85/15; δ=from 0.85 to 0.95 (mt: 3H); from 1.25 to 1.60 (mt: 2H); 1.26and 1.29 (2s: 9H in total); from 2.45 to 2.60 (mt: 0.85H); 2.67 (dd,J=14 and 10 Hz: 0.15H); 2.80 (dd, J=14 and 4.5 Hz: 0.15H); 3.02 (dd,J=14 and 4.5 Hz: 0.85H); from 3.20 to 3.35 (mt: 1H); 3.52 (mt: 0.85H);3.69 (mt: 0.15H); 4.61 (d, J=6 Hz: 0.15H); 4.71 (d, J=6 Hz: 0.85H); 6.41(d, J=9.5 Hz: 0.15H); 6.62 (d, J=9.5 Hz: 0.85H); 7.20 (d, J=6 Hz: 1.7H);7.23 (d, J=6 Hz: 0.3H); from 8.35 to 8.50 (mt: 2H in total)].

Tert-Butyl N-[(1R)-2-oxo-(4-pyridylmethyl)-butyl]carbamate: 50 cm³ of a3N solution of ethyl magnesium bromide dissolved in diethyl ether areadded over 1 hour to a mixture, under an inert atmosphere, of 14 g oftert-butylN-{2-[N-methoxy-N-(methyl)amino]-2-oxo-(1R)-1-(4-pyridylmethyl)ethyl}carbamatein 350 cm³ of tetrahydrofuran, cooled to a temperature in the region of0° C. After stirring for 48 hours at 0° C., water is added to thereaction medium, the resulting mixture is extracted with dichloromethaneand the extracts are washed with water. The organic phase is dried oversodium sulfate, filtered and then concentrated under reduced pressure (2kPa) at a temperature in the region of 40° C. 10.5 g of tert-butylN-[(1R)-2-oxo-1-(4-pyridylmethyl)butyl]carbamate are obtained in theform of a yellow oil [¹H NMR spectrum (300 MHz, (CD₃)₂SO-d₆, δ in ppm):0.94 (t, J=7 Hz: 3H); 1.32 (s: 9H); from 2.40 to 2.65 (mt: 2H); 2.70(dd, J=14 and 10.5 Hz: 1H); 3.06 (dd, J=14 and 4.5 Hz: 1H); 4.22 (mt:1H); 7.26 (broad d, J=5.5 Hz: 2H); 7.44 (broad d, J=8 Hz: 1H); 8.45(broad d, J=5.5 Hz: 2H)].

EXAMPLE 33 (4R)-4-(2-Thienylmethyl)-4,5-dihydro-2-thiazolylaminehydrochloride

0.9 cm³ (9.4 mmol) of ethyl chloroformate is added dropwise to asolution of 2.5 g (9.23 mmol) of Boc-D-2-thienylalanine and 1.3 cm³ (9.4mmol) of triethylamine in 100 cm³ of anhydrous tetrahydrofuran at −20°C. The resultant suspension is stirred at −20° C. for 1 hour and thenfiltered. The filtrate is cooled to −20° C. and a solution of 0.71 g(20.9 mmol) of sodium borohydride in 5 cm³ of water is then added. Thereaction mixture is stirred at a temperature in the region of 20° C. for64 hours and is then concentrated under vacuum to give a residue whichis used directly without purification. A suspension of the productobtained in 20 cm³ of dioxane is treated with 6 cm³ of a 4M solution ofhydrochloric acid in dioxane and is then stirred at a temperature in theregion of 20° C. for 16 hours. After concentrating the reaction mediumunder vacuum, 7.5 g of a white solid are obtained and are used directlywithout purification.

A suspension of the above product (1.0 g), triethylamine (4 cm³, 28.7mmol) and tert-butyl isothiocyanate (0.50 g, 4.3 mmol) in 10 cm³ ofethanol is heated at a temperature in the region of 50° C. for 4 hourswith stirring. After concentrating under vacuum, the residue is taken uptwice in 50 cm³ of ethyl acetate and is then purified by chromatographyon a column of silica gel (ethyl acetate/cyclohexane 1/1 by volume). Thefractions containing the expected product are concentrated under reducedpressure to give 255 mg of a white solid which is used directly.

A suspension of the product obtained above (240 mg, 0.88 mmol) isrefluxed in 6 cm³ of 6N hydrochloric acid solution for 8 hours. Thereaction mixture is concentrated to dryness under vacuum and the brownresidue is slurried in a mixture of ethanol (5 cm³) and ethyl acetate (3cm³) and then filtered. This slurrying operation is repeated 3 times,until a clear yellow solution is obtained. After partial concentration,the product crystallizes and is filtered off and then dried under vacuumto give 64 mg of (4R)-4-(2-thienylmethyl)-4,5-dihydro-2-thiazolylaminehydrochloride in the form of pale yellow crystals melting at 125-127° C.[¹H NMR spectrum (300 MHz, (CD₃)₂SO-d₆, δ in ppm): 10.1 (bs, 1H), 9.7(bs, 1H), 9.3 (bs, 1H), 7.4 (m, 1H), 7.0 (m, 2H), 4.5 (m, 1H), 3.6 (m,1H), 3.3 (m, 1H), 3.2 (m, 2H)].

The pharmaceutical compositions according to the invention consist of acompound of formula (I) or an isomer or tautomer or salt of such acompound, in pure form or in the form of a composition in which it iscombined with any other pharmaceutically compatible product, which maybe inert or physiologically active. The medicinal products according tothe invention may be used orally, parenterally, rectally or topically.

Solid compositions for oral administration which can be used includetablets, pills, powders (gelatin capsules, cachets) or granules. Inthese compositions, the active principle according to the invention ismixed with one or more inert diluents, such as starch, cellulose,sucrose, lactose or silica, under a stream of argon. These compositionscan also comprise substances other than diluents, for example one ormore lubricants such as magnesium stearate or talc, a dye, a coating(dragee) or a varnish.

Liquid compositions for oral administration which can be used includepharmaceutically acceptable solutions, suspensions, emulsions, syrupsand elixirs containing inert diluents such as water, ethanol, glycerol,plant oils or liquid paraffin. These compositions can comprisesubstances other than diluents, for example wetting products,sweeteners, thickeners, flavorings or stabilizers.

The sterile compositions for parenteral administration can preferably beaqueous or non-aqueous solutions, suspensions or emulsions. Solvents orvehicles which may be used include water, propylene glycol, apolyethylene glycol, plant oils, in particular olive oil, injectableorganic esters, for example ethyl oleate, or other suitable organicsolvents. These compositions can also contain adjuvants, in particularwetting agents, isotonic agents, emulsifiers, dispersants andstabilizers. The sterilization can be carried out in several ways, forexample by aseptic filtration, by incorporating sterilizing agents intothe composition, by irradiation or by heating. They can also be preparedin the form of sterile solid compositions which can be dissolved at thetime of use in sterile water or any other injectable sterile medium.

The compositions for rectal administration are suppositories or rectalcapsules which contain, besides the active product, excipients such ascocoa butter, semisynthetic glycerides or polyethylene glycols.

Compositions for topical administration can be, for example, creams,lotions, eye drops, mouth washes, nasal drops or aerosols.

In human therapy, the compounds according to the invention areparticularly useful for treating and/or preventing multiple sclerosis,cerebral, focal or global ischemia, cerebral or spinal trauma,Parkinson's disease, Huntington's diseases, Alzheimer's disease,amyotrophic lateral sclerosis, migraine, depression, schizophrenia,anxiety, epilepsy, diabetes, atherosclerosis, myocarditis, arthritis,arthrosis, asthma, irritable bowel syndrome, Crohn's disease,peritonitis, gastro-esophageal reflux, uveitis, Guillain-Barré0syndrome, glomerulonephritis, lupus erythematosus, psoriasis, the growthof certain forms of tumors such as, for example, epithelioma,adenocarcinoma or sarcoma, and in infections with Gram-positive orGram-negative intracellular or extracellular bacteria.

The doses depend on the desired effect, the duration of the treatmentand the route of administration used; they are generally between 1 mgand 100 mg per day via the oral route for an adult, with unit dosesranging from 0.5 mg to 50 mg of active substance.

In general, the doctor will determine the appropriate dosage as afunction of the age, weight and all the other personal factors of theindividual to be treated.

The examples which follow illustrate compositions according to theinvention:

Example A

Gel capsules containing a 50 mg dose of active product and having thecomposition below are prepared, according to the usual technique:

Compound of formula (I) 50 mg Cellulose 18 mg Lactose 55 mg Colloidalsilica  1 mg Sodium carboxymethylstarch 10 mg Talc 10 mg Magnesiumstearate  1 mg

Example B

Tablets containing a 50 mg dose of active product and having thecomposition below are prepared according to the usual technique:

Compound of formula (I)  50 mg Lactose 104 mg Cellulose  40 mgPolyvidone  10 mg Sodium carboxymethylstarch  22 mg Talc  10 mgMagnesium stearate  2 mg Colloidal silica  2 mg

Mixture of hydroxymethylcellulose, glycerol and titanium oxide(72/3.5/24.5) qs 1 finished film-coated tablet weighing 245 mg.

Example C

An injectable solution containing 10 mg of active product and having thecomposition below is prepared:

Compound of formula (I)   10 mg Benzoic acid   80 mg Benzyl alcohol 0.06ml Sodium benzoate   80 mg 95% ethanol  0.4 ml Sodium hydroxide   24 mgPropylene glycol  1.6 ml Water qs 4 ml

The present invention also relates to the method for preventing andtreating diseases in which an abnormal production of nitric oxide (NO)by induction of inducible NO-synthase (NOS-2 or iNOS) is involved byadministration of a compound of formula (I), racemic mixtures,enantiomers and diastereoisomers thereof and mixtures thereof, thetautomer thereof or pharmaceutically acceptable salts thereof.

What is claimed is:
 1. A compound of the formula (I):

wherein R₁ is hydrogen or C₁₋₆alkyl; and R₂ is —CH₂—R₃; and wherein R₃is thienyl, thiazolyl, imidazolyl, or triazolyl; or a racemic mixture,an enantiomer, a diastereoisomer or a mixture thereof, or a tautomerthereof, or a pharmaceutically acceptable salt thereof.
 2. The compoundaccording to claim 1, wherein R₃ is thienyl or imidazolyl.
 3. Thecompound according to claim 1, wherein R₃ is 2 or 3- thienyl, 4- or5-thiazolyl, 1-imidazolyl or 1-triazolyl.
 4. The compound according toclaim 2, wherein R₃ is 2 or 3- thienyl or 1-imidazolyl.
 5. The compoundaccording to claim 1, which is chosen from the following:4-(3-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,4-(2-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,4-(4-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,4-(1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,4-(5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,4-(1-triazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine, or a racemicmixture, an enantiomer, a diastereoisomer or a mixture thereof, or atautomer thereof, or a pharmaceutically acceptable salt thereof.
 6. Thecompound according to claim 1, which is chosen from the following:(−)-(4R)-4-(3-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,(4R)-4-(2-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,(+)-4-(5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,(−)-4-(5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,(4R)-4-(1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,(4S)-4-(1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,(+)-(4R)-4-(4-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,(+)-4-(1-triazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine, or atautomer thereof, or a pharmaceutically acceptable salt thereof.
 7. Thecompound according to claim 2, which is chosen from the following:4-(3-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,4-(2-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,4-(1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine, or a racemicmixture, an enantiomer, a diastereoisomer or a mixture thereof, or atautomer thereof, or a pharmaceutically acceptable salt thereof.
 8. Thecompound according to claim 2, which is chosen from the following:(−)-(4R)-4-(3-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,(4R)-4-(2-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,(4R)-4-(1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,(4S)-4-(1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine, or atautomer thereof, or a pharmaceutically acceptable salt thereof.
 9. Apharmaceutical composition comprising, as active ingredient, at leastone compound of formula (I):

wherein R₁ is hydrogen or C₁₋₆alkyl; and R₂ is —CH₂—R₃; and wherein R₃is thienyl, thiazolyl, imidazolyl, or triazolyl; or a racemic mixture,an enantiomer, a diastereoisomer or a mixture thereof, or a tautomerthereof, or a pharmaceutically acceptable salt thereof.
 10. Thecomposition according to claim 9 wherein R₃ is thienyl or imidazolyl.11. The composition according to claim 9, wherein R₃ is 2 or 3-thienyl,4- or 5-thiazolyl, 1-imidazolyl or 1-triazolyl.
 12. The compositionaccording to claim 10, wherein R₃ is 2 or 3-thienyl or 1-imidazolyl. 13.The composition according to claim 9 wherein said compound is selectedfrom the group consisting of:4-(3-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,4-(2-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,4-(4-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,4-(1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,4-(5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine, and4-(1-triazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine, or a racemicmixture, an enantiomer, a diastereoisomer or a mixture thereof, or atautomer thereof, or a pharmaceutically acceptable salt thereof.
 14. Thecomposition according to claim 9 wherein said compound is selected fromthe group consisting of:(−)-(4R)-4-(3-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,(4R)-4-(2-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,(+)-4-(5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,(−)-4-(5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,(4R)-4-(1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,(4S)-4-(1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,(+)-(4R)-4-(4-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine, and(+)-4-(1-triazolylmethyl)-4,5-dihiydro-1,3-thiazol-2-ylamine, or atautomer thereof, or a pharmaceutically acceptable salt thereof.
 15. Thecomposition according to claim 10 wherein said compound is selected fromthe group consisting of:4-(3-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,4-(2-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine, and4-(1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine, or a racemicmixture, an enantiomer, a diastereoisomer or a mixture thereof, or atautomer thereof, or a pharmaceutically acceptable salt thereof.
 16. Thecomposition according to claim 10 wherein said compound is selected fromthe group consisting of:(−)-(4R)-4-(3-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,(4R)-4-(2-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,(4R)-4-(1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,(4S)-4-(1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine, or atautomer thereof, or a pharmaceutically acceptable salt thereof.
 17. Aprocess for preparing a compound of formula (I), including a racemicmixture, an enantiomer, a diastereoisomer or a mixture of saidenantiomer or said diastereomer, or a tautomer thereof:

comprising the step of cyclizing a compound of formula (II) undersuitable acidic reaction conditions such that said compound of formula(II) cyclizes to form said compound of formula (I);

and isolating said compound of formula (I); wherein R₁ is hydrogen orC₁₋₆alkyl; and R₂ is —CH₂—R₃; and wherein R₃ is thienyl, thiazolyl,imidazolyl, or triazolyl.
 18. The process according to claim 17 whereinsaid process includes an additional step comprising converting saidcompound of formula (I) into a pharmaceutically acceptable salt by wayof a reaction of said compound with a suitable inorganic or organicacid.
 19. A process for the preparation of the compound of formula (II)as defined in claim 17 and in which R₁ is hydrogen, comprising the stepsof: reacting a compound of formula (IIa)

with a suitable reducing agent under suitable reaction conditions toform the compound of formula (IIb)

reacting said compound of formula (IIb) with a suitable deprotectingagent to form a compound of formula (IIc)

reacting said compound of formula (IIc) with tert-butyl thiocyanate toform said compound of formula (II); wherein R₂ is as defined in claim17; and Ra is either hydrogen or an amino protecting group.
 20. Aprocess for preparing a compound of formula (I) according to claim 1,for which R₂ is —CH₂—R₃ wherein R₃ is 1-imidazolyl or1-(1,2,4-triazolyl) radical, comprising the step of reacting imidazoleor 1,2,4-triazole with a derivative of formula (IV):

wherein R₁ has the same meaning as in claim 1, X is halogen or tosylradical and Ra and Rb are hydrogen or protecting groups for the aminefunction, optionally followed by a deprotection, and isolating theproduct.
 21. The process according to claim 20 wherein said processincludes an additional step comprising converting said compound offormula (I) into a pharmaceutically acceptable salt by way of a reactionof said compound with a suitable inorganic or organic acid.